Methods and tools for identification of rsk/msk kinase inhibitors

ABSTRACT

The present invention concerns 3D-crystals of complexes of ribosomal S6 kinase (RSK) and mitogen- and stress-activated protein kinase (MSK) proteins and their ligands, as well as methods for crystallisation, three-dimensional structure determination and structure assisted methods for identifying ligands of said proteins.

FIELD OF INVENTION

The present invention relates to the field of structure assisted drug design. More specifically the present invention relates to the field of identification and development of novel RSK and MSK kinase inhibitors by X-ray crystallographic methods and subsequent in silico, in vitro and in vivo screening methods for identification of candidate inhibitors of RSK/MSK.

BACKGROUND OF INVENTION

Fumaric acid esters (FAE) are a group of compounds beneficial in systemic treatment of psoriasis and recently FAEs have also been suggested as a new therapeutic option to treat relapsing remitting multiple sclerosis⁷⁻⁹.

Various combinations of FAEs for oral treatment of psoriasis have been used for more than 50 years^(10,11). Although a controlled study demonstrated the efficacy of dimethylfumarate (DMF) in psoriasis in 1989¹², it was an empirically composed mixture of dimethylfumarate (DMF) with calcium, magnesium and zinc salts of ethylhydrogen fumarate that was registered as Fumaderm® in Germany in 1994. Fumaderm® has since then become the leading drug for systemic therapy of psoriasis in Germany¹¹. One limitation in the use of FAE's is the reported side effects with flushing and gastrointestinal symptoms such as diarrhoea, nausea and cramps. Thus, overall FAE's have been shown to have a favourable long-term safety and clinical-efficacy profile² and in particular no long-term toxicity nor a higher risk for infections or malignancies have been observed in more than 100,000 patient years.

A second generation fumaric acid derivative (BG-12) was developed as an enteric-coated microtablet to improve gastrointestinal tolerability¹³. BG-12 has shown very promising result in patients with relapsing-remitting multiple sclerosis in a multi-centre, randomized, double-blind, placebo-controlled phase IIb study^(9,14) and most recently two phase III clinical trials in patients with relapsing-remitting multiple sclerosis including more than 2600 patients have been reported to confirm these results although the complete data set has not yet been published¹⁵.

Fumaric acid esters have been shown to be effective in several dermatological diseases including: Necrobiosis¹⁶⁻¹⁹, granuloma annulare^(18,20-22,) alopecia areata²³, cheilitis granulomatosa^(18,24), recurrent oral aphthae²⁵ , pityriasis rubra pilaris¹⁸, and annular elastolytic giant cell granuloma¹⁸, as well as a range of non-dermatological diseases: Sarcoidosis^(18,26) and non-infectious chronic uveitis²⁷. Fumaric acid esters have also shown potential for the use in treatment of cancer²⁸⁻³⁰, Huntington's disease³¹, malaria³², human immunodeficiency virus³³, bronchial asthma³⁴, myocardial infarction³⁵ and for use as an immunosuppressor in organ transplantation³⁶.

Despite a clear clinical effect of FAE's in psoriasis and relapsing-remitting multiple sclerosis and numerous in vitro and in vivo studies with FAE's, the precise mechanism of action had not been fully understood. FAEs have been shown to inhibit the expression of TNF-α induced adhesion molecules³⁷ as well as various cytokines including psoriasis associated cytokines like IL-1β, IL-6, IL-8, IL-20 and TNF-α³⁸⁻⁴⁰. DMF also suppresses the expression of VEGFR2 in human endothelial cells indicating a possible anti-angiogenic action⁴¹. Other possible mechanisms causing an anti-psoriatic effect are FAE induced apoptosis of purified human T-cells⁴² and a FAE induced shift in the immunological balance from a Th1- towards a Th2-like⁴³. Because there is a lack of detectable DMF plasma concentrations after oral intake it has been suggested that there is a reaction of DMF with glutathione (GSH) in the portal vein blood⁴⁴. This hypothesis has recently been supported by novel findings of Ghoreschi and co-workers⁴⁵.

Both multiple sclerosis (MS) and psoriasis are considered autoimmune CD4+ T-cell driven disorders with predominance of a Th1 and Th17 phenotype of pathogenic T-cells⁴⁶. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) bridging innate and acquired immunity, recognizing infections, secreting proinflammatory cytokines and orchestrating the maturation of naïve T-cells and to create the cytokine microenvironment regulating T-cell differentiation⁴⁷. FAE have previously been shown to induce a shift in the immunological balance from a Th1-toward a Th2-like response⁴³ and to inhibit the differentiation of dendritic cells⁴⁸. More recently Ghoreschi et al. 2011⁴⁵ suggested that DMF depletes glutathione (GSH) followed by increased hemoxygenase-1 (HO-1) expression and impared STAT1 phosphorylation. HO-1 interact with AP-1 and NF-κB binding sites in the IL-23p19 promoter inhibiting its expression and IL-23 is a key driver of Th17 maturation. STAT1 inhibition prevented IL-12p35 expression leading to decreased expression of the Th1 driver, IL-12. It was therefore suggested that DMF improved MS and psoriasis through inhibition of Th1 and Th17 responses. In this model, the DMF induced GSH depletion is essential.

In opposition to this, several studies have shown that DMF induces a transient GSH depletion whereas prolonged exposure raised GSH expression¹¹ and therefore depletion of GSH cannot account for all the effects of DMF seen in MS and psoriasis. However, regulation of T-cell differentiation is important in controlling these two diseases and it is therefore interesting that a recent study⁵⁹ has demonstrated DMF mediated inhibition of Th1 and Th17 differentiation through suppression of NF-κB and the p38 MAPK-MSK1 and ERK1/2-MSK1 signalling pathways^(39,46). Both NF-κB and MAPK activation have previously been shown to contribute to LPS mediated DC maturation ^(49,50) Although the ERK1/2 MAPK and the NF-κB pathways are independent, they can interact via MSK1. MSK1 enhances NF-κB transcriptional activity through phosphorylation of serine 276 of the NF-κB subunit, p65. Further MSK1 phosphorylates Histone-3 at serine 10 which also enhances NF-κB transcriptional activity. The present inventors and others have previously demonstrated an inhibitory effect of DMF on different signaling pathways including the p38 MAPK-MSK1, ERK1/2-RSK1 and MSK1-NF-κB pathways^(36,39,59).

DMF has previously been shown to block the activation of the Ribosomal S6 Kinase family (composed of RSK1 to RSK4 and the homologous kinases MSK1 and MSK2) by the extracellular signal-regulated kinase (ERK)^(39,46).

MSK1/2 and RSK1/2 have overlapping effects on transcription factors like the cAMP-responsive element (CREB), ATF1 and Histone 3⁴⁶, while RSK1 to RSK4 separately regulate the phosphorylation of c-Fos, c-Jun and JunB. The complexes of c-Fos, c-Jun and JunB, formed as dimers, bind to the activator 1 (AP-1) site and AP-1 DNA binding activity regulates cell proliferation ⁵⁴. The specific inhibitory effect of DMF on RSK1 and MSK1 activation followed by the induction of p-c-Jun (S63) and p-p53 (S15) led to the inhibition of keratinocyte proliferation, partly explaining the anti-psoriatic effect of DMF⁴⁶. The specificity of DMF's inhibitory effect on RSK1 and MSK1 activation was proved by transfection with small interfering RSK1 and MSK1 RNA instead of DMF which showed the same effects on induction of p-c-Jun (S63) and p-p53 (S15)⁴⁶.

MSK1/2 and RSK1-4 are activated by pro-inflammatory cytokines and growth factors and their activity is controlled by multiple phosphorylation sites^(55, 56). The serine and threonine kinase activity of MSK1/2 and RSK1-4 is dependent on full length activation by phosphorylation at multiple sites in MSK1/2 and RSK1-4 ⁵⁷. The alignment of the amino acid sequences shows 43% homology between MSK1/2 and RSK1-4 ⁵⁸.

MSKs and RSKs are composed of two kinase domains (a N- and a C-terminal) and are activated by either p38 MAPKs and ERK 1/2 for MSK1/2 or only by ERK1/2 for RSK1-4⁵⁵⁻⁵⁷. The activation starts for both MSKs and RSKs in a similar way by phosphorylation of an activation loop in the C-terminal kinase domain. This phosphorylation leads to the activation of the hydrophobic linker loop in the middle part and then the N-terminal kinase domain is phosphorylated. The N-terminal kinase domain binds and phosphorylates substrates. DMF has been shown to fully inhibit activation of specific phosphorylation sites at the C-terminal domain, in the linker loop and in the N-terminal domain and this reduced the kinase activity of the N-terminal domain and thereby downstream substrate activations^(39,46,51).

The MSK/RSK kinases are composed of two catalytic domains (an N- and a C-terminal) separated by a ˜100 amino acid linker. Each of the catalytic domains is composed of a small N-terminal lobe comprising β-sheets and a larger C-terminal lobe mainly comprising α-helices. ATP and substrate are bound in the interface between the two lobes. The kinases are activated by ERK by phosphorylation of an activation loop in the C-terminal catalytic domain. This phosphorylation leads to the activation of the N-terminal catalytic domain by phosphorylation of the linker region. Phosphorylation of the linker region is abolished by DMF and the activation of the N-terminal kinase domain hereby reduced^(39,46). An apo-structure of the C-terminal kinase domain of murine RSK2 was previously described but does not provide any insights to the binding of ligands (e.g. ATP and substrate). Some RSK2 inhibitors have been identified including Staurosporine like compounds⁴⁸, kaemperol-glycosides⁴⁹ and ⁵⁰s. The majority of the identified RSKs inhibitors are ATP-competitive and bind in the ATP pocket between the two lobes in either one or both of the catalytic domains. An irreversible RSK2 inhibitor of the C-terminal catalytic domain has been developed, covalently binding to a cysteine located in the ATP pocket^(51,52).

ATP-competitive inhibitors generally display reduced selectivity due to the numerous ATP-binding pockets in the cell and poor cellular activity due to the high intracellular ATP concentration. The development of an allosteric RSK/MSK inhibitor will reduce off-target effects and increase efficacy. DMF can form covalent adducts with intracellular thiol containing molecules such as GSH, whereas a RSK/MSK selective inhibitor will only undergo covalent interaction once bound in the allosteric pocket.

SUMMARY OF INVENTION

The present inventors have elucidated the structural basis for the mechanism of action of DMF inhibition of the RSK and MSK families of kinases. A 1.9 Å resolution X-ray crystal structure of the C-terminal kinase domain of murine RSK2 co-crystallized with DMF revealed the binding of one DMF molecule to RSK2. A conserved cysteine residue modified by a covalent Michael-addition to DMF defines the binding site (FIG. 1). The binding site is situated in a hinge region (FIG. 2). Comparison with X-ray structures of related kinases revealed that the hinge region will undergo large structural rearrangements during activation, and that covalent modification of the cysteine in the hinge region could abolish this by steric hindrance or by stabilizing the interaction between the C-terminal helix-bundle and the inhibitory αL-helix (FIG. 2). The covalent modification of the conserved cysteine was confirmed by mass spectrometry analysis (FIG. 3). The importance of the binding of DMF to the conserved cysteine in the hinge region was underscored by mutational studies of RSK2 and MSK1 in cell cultures. Mutation of the cysteine, which is conserved across the RSK and MSK families, to a valine abolished the effect of DMF (FIG. 4).

The inventors have thus been able to describe the mechanism behind DMF binding in RSK and MSK families. This has been achieved by the findings of the appropriate conditions for growing highly ordered three-dimensional crystals of the RSK2 protein. Based on these findings, the inventors have developed a method for identifying candidate inhibitors of RSK and MSK proteins.

The basis for identification of ligands according to the present invention is to obtain a crystal of sufficient quality for high resolution X-ray crystallography.

Accordingly, in a main aspect, the present invention concerns a three dimensional crystal of a complex between:

a) one or more fumaric acid ester derivative ligands, and b) a polypeptide comprising the sequence of SEQ ID NO: 1 (C-terminal kinase domain of murine ribosomal S6 kinase 2), or a biologically active structural and/or functional variant thereof, wherein the biological activity is kinase activity.

In another aspect the present invention concerns a three dimensional crystal of a ribosomal S6 kinase (RSK) or a mitogen- and stress-activated protein kinase (MSK) polypeptide bound to one or more ligands.

More specifically the invention concerns a three dimensional crystal of a polypeptide bound to one or more ligands, wherein the polypeptide has:

-   -   a) an amino acid sequence selected from the group consisting of         SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,         16, 17, 18. 19 or 20; or     -   b) a sequence variant of the polypeptide of a), wherein the         sequence variant has at least 70% sequence identity to SEQ ID         NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,         17, 18. 19 or 20; or     -   c) a fragment of the polypeptide of a) or b), wherein the         fragment comprises at least 200 contiguous amino acids of any         one of a) or b), and wherein the biological activity is kinase         activity.

Growing of highly ordered protein crystals capable of diffracting X-rays to atomic resolution is far from straight forward. However the present inventors have succeeded in developing a protocol suitable for growing RSK2 crystals.

Hence, in one aspect, the present invention concerns a method for growing the above defined crystal, comprising the steps of:

-   -   a) obtaining a composition comprising 2 to 15 mg/mL, such as 5         to 12 mg/mL, such as 5 to 10 mg/mL of a polypeptide selected         from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8,         9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 or a fragment         or variant thereof, in a suitable buffer,     -   b) contacting the composition of a) with a ligand,     -   c) allowing time for formation of a protein-ligand complex in         solution,     -   d) mixing the solution comprising the protein-ligand complex         of c) with a reservoir solution comprising a precipitant and a         buffer,     -   e) incubating a drop of the mixture of d) under vapour diffusion         conditions versus the reservoir solution,     -   f) obtaining crystals of the protein-ligand complex.

The solution of the structure of RSK2 in complex with DMF has allowed the present inventors to develop a method for screening for candidate compounds capable of binding to RSK2 and homologous kinases, with the aim of inhibiting the kinase activity of these enzymes.

Thus in one aspect the present invention concerns a computer-based method for rational drug design which comprises:

-   -   a) providing the atomic coordinates of the polypeptide as         defined by the coordinates of table 3;     -   b) providing the structure of a candidate inhibitor molecule;         and     -   c) fitting the structure of candidate inhibitor molecule to the         atomic coordinates of the polypeptide of said table.

In another aspect the invention concerns a computer-based method for identifying a potential inhibitor of the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 comprising the steps of:

-   -   a) employing a three-dimensional structure of the polypeptide,         the three-dimensional structure being defined by atomic         coordinate data according to table 3; and     -   b) identifying the potential inhibitor by designing or selecting         a compound for interaction with the active site.

The invention also concerns a computer readable media with either (a) atomic coordinate data according to table 3 recorded thereon, said data defining the three-dimensional structure of the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, at least one atom or at least one sub-domain thereof, or (b) structure factor data for the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 recorded thereon, the structure factor data being derivable from the atomic coordinate data of table 3.

In one aspect the invention concerns a computer-readable data storage medium comprising a data storage material encoded with at least a portion of the structure coordinates set forth in table 3.

In another aspect the invention concerns a method for identifying a ligand capable of binding to the binding site of SEQ ID NO. 1 (C-terminal domain of murine RSK2), said method comprising the steps of:

-   -   a) generating the spatial structure of the binding site on a         computer screen using atomic coordinates as presented in table 3         or atomic coordinates selected from a three-dimensional         structure that deviates from the three-dimensional structure         presented in table 3 by a root mean square deviation over         protein backbone atoms of not more than 3 Å,     -   b) generating potential ligands with their spatial structure on         the computer screen, and     -   c) selecting ligands that can bind to at least 1 amino acid         residue of the set of binding interaction sites without steric         interference.

In yet another aspect the invention concerns a computer-assisted method for identifying a ligand of a polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, using a programmed computer comprising a processor, a data storage system, a data input device and a data output device, comprising the following steps:

-   -   a) inputting into the programmed computer through said input         device data comprising:         -   atomic coordinates of a subset of the atoms of said             polypeptide, thereby generating a criteria data set;         -   wherein said atomic coordinates are selected from the             three-dimensional structure presented in table 3 or atomic             coordinates selected from a three-dimensional structure that             deviates from the three-dimensional structure presented             table 3 by a root mean square deviation over protein             backbone atoms of not more than 3 Å,     -   b) comparing, using said processor, the criteria data set to a         computer data base of low-molecular weight organic chemical         structures and peptide fragments stored in the data storage         system; and     -   c) selecting from said database, using computer methods, a         chemical structure having a portion that is structurally         complementary to the criteria data set and being free of steric         interference with the polypeptide selected from the group         consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,         13, 14, 15, 16, 17, 18, 19 and 20.

In another aspect the invention concerns a method for identifying a ligand, said method comprising the steps of:

-   -   a) selecting a potential ligand using atomic coordinates in         conjunction with computer modelling, wherein said atomic         coordinates are the atomic coordinates presented in table 3 or         wherein the atomic coordinates are selected from a         three-dimensional structure that deviates from the         three-dimensional structure presented in any of table 3 by a         root mean square deviation over protein backbone atoms of not         more than 3 Å, by docking potential ligands into a set of         binding interaction sites the binding site of said polypeptide         selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5,         6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, said         binding interaction generated by computer modelling and         selecting a potential ligand capable of binding to at least one         amino acid in said set of binding interaction sites of said         polypeptide selected from the group consisting of SEQ ID NO. 1,         2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19         and 20,     -   b) providing said potential ligand and said polypeptide,     -   c) contacting the potential ligand with said polypeptide and     -   d) detecting binding of said polypeptide by the potential         ligand.

DESCRIPTION OF DRAWINGS

FIG. 1: Atomic structure of RSK2 in complex with dimethyl fumarate (DMF). The covalent modification of cysteine 599 (C599) with DMF in the hinge region of RSK2. The 2Fo-Fc electron density map is contoured at 1.0σ.

FIG. 2: Mechanism of action of DMF modification of C599.

Activation of RSK2 (light grey) by ERK leads to the phosphorylation of a threonine residue in the activation loop (grey). The movement of activation loop has been determined by X-ray crystallography for several kinases and is shown for the related kinase CDK2 (dark grey). The hinge region is undergoing large structural rearrangements during activation and modification of C599 could abolish this by steric hindrance.

FIG. 3: Mass spectrometric analysis of DMF modification of RSK2 at cysteine 599 (C599). Covalent modification of C599 was identified by chymotrypsin treatment of RSK2. The carbamidomethylated KRQGYDAACDIW peptide of RSK2 containing C599 was identified as 1482.73 and 1514.73 (dioxidized). DMF modification of the peptide was identified as 1569.73 and 1601.69 (dioxidized).

FIG. 4: The importance of the binding of dimethyl fumarate (DMF) to the cysteine in the hinge region (C599) was underscored by mutational studies of RSK2 and MSK1 in HEK 293 cell cultures stimulated by epidermal growth factor (EGF). Mutation studies of RSK2 in cell cultures stimulated by EGF showed that mutation of cysteine (C599) to valine abolished the effect of DMF, as no decrease in the phosphorylation of S386 was observed (representative blot: 4A, statistical analysis: 4B). Mutation of the cysteine corresponding to C599 in MSK1 (C603) to a valine abolished the effect of DMF, as no decrease in the phosphorylation of S376 was observed (representative blot: 4C, statistical analysis: 4D).

FIG. 5: Multiple sequence alignment of sequence 1-20 aligned in MUSCLE⁶⁰. Fully conserved positions are depicted in black, 50% conserved positions in dark gray and less than 50% conserved positions depicted in light gray.

DETAILED DESCRIPTION OF THE INVENTION

The term “crystal” refers to an ordered state of matter. Proteins, by their nature are difficult to purify to homogeneity. Even highly purified proteins may be chronically heterogeneous due to modifications, the binding of ligands or a host of other effects.

In addition, proteins are crystallized from generally complex solutions that may include not only the target molecule but also buffers, salts, precipitating agents, water and any number of small binding proteins. It is important to note that protein crystals are composed not only of protein, but also of a large percentage of solvents molecules, in particular water. These may vary from 30 to even 90%. Protein crystals may accumulate greater quantities and a diverse range of impurities which cannot be listed here or anticipated in detail. Frequently, heterogeneous masses serve as nucleation centers and the crystals simply grow around them. The skilled person knows that some crystals diffract better than others. Crystals vary in size from a barely observable 20 micron to 1 or more millimetres. Crystals useful for X-ray analysis are typically single, 0.05 mm or larger, and free of cracks and defects.

The term “coordinate” as use herein, refers to the information of the three dimensional organization of the atoms contributing to a protein structure. The final map containing the atomic coordinates of the constituents of the crystal may be stored on a data carrier; typically the data is stored in PDB format. However, crystal coordinates may as well be stored in simple tables or text formats. The PDB format is organized according to the instructions and guidelines given by the Research Collaboratory for Structural Bioinformatics (RCSB).

The term “root mean square deviation” (rmsd) is used as a mean of comparing two closely related structures and relates to a deviation in the distance between related atoms of the two structures after structurally minimizing this distance in an alignment. Related proteins with closely related structures will be characterized by relatively low RMSD values whereas larger differences will result in an increase of the RMSD value.

The term “associating with” or “binding” refers to a condition of proximity between chemical entities or compounds, or portions thereof. The association may be non-covalent—wherein the juxtaposition is energetically favoured by hydrogen bonding or van der Waals or electrostatic interactions- or it may be covalent.

The term “binding pocket”, as used herein, refers to a region of a molecule or molecular complex that, as a result of its shape, favourably associates with another molecule, molecular complex, chemical entity or compound.

As used herein the term “complex” refers to the combination of a molecule or a protein, conservative analogues or truncations thereof associated with a chemical entity.

RSK/MSK Crystal

An aspect of the invention relates to a crystal which comprises a RSK/MSK kinase.

Depending on the resolution of a crystal structures larger differences information can be obtained from the data. At a resolution of about 5.5 Å the overall shape of a molecule, such as helices are visible with strong density. At a resolution of about 3.5 Å the overall features of the polypeptide backbone becomes visible (usually with some ambiguities). At a resolution of about 3 Å the side chains are partly resolved and at a resolution of about 2.5 Å the side chains are well resolved. The atoms are located within about 0.4 Å meaning that the lengths of hydrogen bonds calculated from a PDB file (using e.g. for example, by PyMol) have at least this uncertainty. The limit of protein crystallography is normally around 1.5 Å, where atoms are located to about ±0.1 Å. In rare cases do protein crystals diffract better than 1 Å resolution yielding an accuracy of the atomic positions below 0.1 Å, comparable to crystal structures of small molecules.

The crystal of the invention preferably effectively diffracts x-rays for the determination of the atomic coordinates of the protein to a resolution better than 6 Å. More preferably the three dimensional structure determinations can be determined with a resolution of more than 5 Å, such as more than 4 Å or most preferably about 3.5 A using the crystals according to the invention. Most preferably the crystal effectively diffracts x-rays for the determination of the atomic coordinates of the protein to a resolution of 3.6 Å

The space group of the crystal according to the invention is P4₁2₁2 and the cell dimensions are preferably a=b=46.6±4 Å and c=289.5±4 Å. The cell dimensions can vary depending on the specific RSK/MSK comprised by the crystal, quaternary structure and also depending on ligand of choice, and also on the conformation of the RSK/MSK comprised by the crystal.

The inventors have been able to describe the mechanism behind DMF binding in RSK and MSK families by finding the appropriate conditions for growing highly ordered three-dimensional crystals of the RSK2 protein. Based on these findings, the inventors have developed a method for identifying candidate inhibitors of RSK and MSK proteins.

Accordingly, in a main aspect, the present invention concerns a three dimensional crystal of a complex between:

a) one or more fumaric acid ester derivative ligands, and b) a polypeptide comprising the sequence of SEQ ID NO: 1 (C-terminal kinase domain of murine ribosomal S6 kinase 2), or a biologically active structural and/or functional variant thereof, wherein the biological activity is kinase activity.

In another aspect, the present invention concerns a three dimensional crystal of a ribosomal S6 kinase (RSK) or a mitogen- and stress-activated protein kinase (MSK) polypeptide bound to one or more ligands.

In yet another aspect, the present invention concerns a three dimensional crystal of a polypeptide bound to one or more ligands, wherein the polypeptide has:

-   -   a) an amino acid sequence selected from the group consisting of         SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,         16, 17, 18. 19 or 20; or     -   b) a sequence variant of the polypeptide of a), wherein the         sequence variant has at least 70% sequence identity to SEQ ID         NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,         17, 18. 19 or 20; or     -   c) a fragment of the polypeptide of a) or b), wherein the         fragment comprises at least 200 contiguous amino acids of any         one of a) or b), and wherein the biological activity is kinase         activity.

The present inventors have found the specific interactions between a fumaric acid ester derivative ligand and the C-terminal kinase domain of murine RSK2, by co-crystallisation. The inventors have found that the ligand is located in a binding site comprising amino acid residues Y197, A200, C201, W204, I235, H263, V264, R269 or L312 of SEQ ID NO. 1.

Based on these findings, the inventors have determined the binding site of fumaric acid ester derivative ligand and analogues thereof in polypeptides homologous to SEQ ID NO: 1 such as polypeptides represented by SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20.

Thus in one embodiment the ligand is located in a binding site comprising amino acid residues Y196, A199, C200, W203, I234, H262, V263, R268 or L311 of SEQ ID NO. 2.

In another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y591, G594, C595, W598, I629, H657, V658, R663 or L705 of SEQ ID NO. 3.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667 or L710 of SEQ ID NO. 4.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, 626, H654, V655, R660 or L702 of SEQ ID NO. 5.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y599, A602, C603, W606, I637, H665, M666, R671 or L714 of SEQ ID NO. 6.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y599, S602, C603, W606, I641, T669, V670, R675 or F722 of SEQ ID NO. 7.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO. 8.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y580, G583, C584, W587, I618, H646, V647, R652 or L694 of SEQ ID NO. 9.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667, L710 of SEQ ID NO. 10.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, I626, H654, V655, R660 or L702 of SEQ ID NO. 11.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y619, A622, C623, W626, I657, H685, M686, R691 or L731 of SEQ ID NO. 12.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y663, S666, C667, W670, I705, T733, V734, R739 or F786 of SEQ ID NO. 13.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO. 14.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y591, G594, C595, W598, I629, H657, V658, R663 or L705 of SEQ ID NO. 15.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667 or L710 of SEQ ID NO. 16.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, I626, H654, V655, R660 or L702 of SEQ ID NO. 17.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y716, A719, C720, W723, I754 or H782 or M783 or R788 or L828 of SEQ ID NO. 18.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y575, A578, C579, W582, I617, T645, V646, R651 and F698 of SEQ ID NO. 19.

In yet another embodiment the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO. 20.

The polypeptide comprised in the crystal defined herein above, is preferably folded to comprise secondary and tertiary structure.

On the primary structure level, the polypeptide comprised in the crystal as defined herein above, may comprise an affinity tag, such as a polyhistidine tag, a GST tag, a HA tag, a Flag tag, a C-myc tag, a HSV tag, a V5 tag, a maltose binding protein tag, a cellulose binding domain tag or any tag known by those of skill in the art.

The polypeptide comprised in the crystal as defined herein above, may also comprise a polyhistidine tags, such as an N-terminal poly-histidine tag or a C-terminal poly-histidine tag.

The polypeptide comprised by the crystal may furthermore comprise a protease cleavage site allowing the affinity tag; such as a Tobacco Etch Virus protease site; to be removed. The removal of the tag is preferably performed prior to crystallisation such that the affinity tag can be removed to obtain a significantly purse sample comprising the polypeptide of choice.

In one embodiment the ligand, comprised in the crystal defined herein above, is selected from the group consisting of dimethyl fumarate (DMF) and dimethyl fumarate derivatives. The derivatives are e.g. ester derivatives, fumaric acid or succinic acid.

In one embodiment the ligand is a kinase inhibitor. As such, the ligand is capable of inhibiting the biological kinase activity of one or more of the polypeptides selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20.

In a preferred embodiment the crystal as defined herein above is of a tetragonal space group, preferably of space group P4₁2₁2.

In one embodiment, the crystal according to the present invention has the crystal unit cell parameters a=b=46.95 Å±4 Å, c=291.30 Å±4 Å and α=β=γ=90°.

In an embodiment the invention relates to a crystal comprising a ribosomal S6 kinase (RSK) or a mitogen- and stress-activated protein kinase (MSK) polypeptide bound to one or more ligands, wherein the ribosomal S6 kinase (RSK) and the mitogen- and stress-activated protein kinase (MSK) polypeptide is from a mammalian species. In a preferred embodiment the polypeptide is of murine or human origin.

The invention further encompasses ribosomal S6 kinase (RSK) or a mitogen- and stress-activated protein kinase (MSK) polypeptide from different species such human and other animals.

Accordingly, the invention also concerns crystals comprising homologues of a predetermined sequence, which homologues preferably have at least 70% sequence identity, such as 75% sequence identity, for example at least 80% sequence identity, such as at least 85% sequence identity, for example at least 90% sequence identity, such as at least 91% sequence identity, for example at least 91% sequence identity, such as at least 92% sequence identity, for example at least 93% sequence identity, such as at least 94% sequence identity, for example at least 95% sequence identity, such as at least 96% sequence identity, for example at least 97% sequence identity, such as at least 98% sequence identity, for example 99% sequence identity with the a sequence selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. 19 and 20.

The per cent identity is determined with the algorithms GAP, BESTFIT, or FASTA in the Wisconsin Genetics Software Package Release 7.0, using default gap weights.

The term “sequence identity” means that two polypeptide sequences are identical (i.e., on a residue-by-residue basis) over the window of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical amino acid residues occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

According to the invention the polypeptide comprised by the crystal is not the necessarily a full-length protein. Truncated versions can readily be prepared by conventional methods of molecular biology (Sambrook and Russell, 2001). According to the invention it is preferred that the polypeptide of the crystal comprise more than 75%, more preferred 80%, and mostly preferred more than 90% of the full length protein sequences.

A homologue comprising fragments of the polypeptide preferably includes least 100, contiguous amino acids of a sequence selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. 19 and 20.

Since two polypeptide sequences may each comprise (1) a portion of the complete polypeptide sequence that is similar between the two polypeptides, and (2) a sequence that is divergent between the two polypeptides, sequence comparisons between two (or more) polypeptides are typically performed by comparing sequences of the two polypeptides over a “comparison window” to identify and compare local regions of sequence similarity. A “comparison window”, as used herein, refers to a conceptual segment of at least 20 contiguous peptide positions wherein a polypeptide sequence may be compared to a predetermined sequence of at least 20 contiguous peptides and wherein the portion of the polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less as compared to the predetermined sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences.

Optimal alignment of sequences for aligning a comparison window may be conducted by the local homology algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2: 482, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48: 443, by the search for similarity method of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. (U.S.A.) 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by inspection, and the best alignment (i.e., resulting in the highest percentage of homology over the comparison window) generated by the various methods is selected.

In a preferred embodiment the crystal includes a homologue of a ribosomal S6 kinase (RSK) or a mitogen- and stress-activated protein kinase (MSK) polypeptide, wherein one ore more of the amino acids residues are conserved or substituted by an amino acid residue with similar properties, e.g. the ribosomal S6 kinase (RSK) or the mitogen- and stress-activated protein kinase (MSK) polypeptide may comprise conserved amino acid substitutions (see below). Preferably more than 1, more than 2, more than 5 AA of the above mentioned AA are conserved or represented by a conserved amino acid substitution. Preferably the ribosomal S6 kinase (RSK) or mitogen- and stress-activated protein kinase (MSK) polypeptide homologue comprised by the crystal comprises all the amino acid residues mentioned herein. Alternatively the ribosomal S6 kinase (RSK) or the mitogen- and stress-activated protein kinase (MSK) polypeptide may comprise conserved amino acid substitutions for one or more of the mentioned amino acid residues.

Conservative amino acid substitutions refer to the inter-changeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine, a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulfur-containing side chains is cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, and asparagine-glutamine.

Additionally, homologues are also determined based on a predetermined number of conservative amino acid substitutions as defined herein below. Conservative amino acid substitution as used herein relates to the substitution of one amino acid (within a predetermined group of amino acids) for another amino acid (within the same group), wherein the amino acids exhibit similar or substantially similar characteristics.

Within the meaning of the term “conservative amino acid substitution” as applied herein, one amino acid may be substituted for another within the groups of amino acids indicated herein below:

-   i) Amino acids having polar side chains (Asp, Glu, Lys, Arg, His,     Asn, Gln, Ser, Thr, Tyr, and Cys,) -   ii) Amino acids having non-polar side chains (Gly, Ala, Val, Leu,     Ile, Phe, Trp, Pro, and Met) -   iii) Amino acids having aliphatic side chains (Gly, Ala Val, Leu,     Ile) -   iv) Amino acids having cyclic side chains (Phe, Tyr, Trp, His, Pro) -   v) Amino acids having aromatic side chains (Phe, Tyr, Trp) -   vi) Amino acids having acidic side chains (Asp, Glu) -   vii) Amino acids having basic side chains (Lys, Arg, His) -   viii) Amino acids having amide side chains (Asn, Gln) -   ix) Amino acids having hydroxy side chains (Ser, Thr) -   x) Amino acids having sulphor-containing side chains (Cys, Met), -   xi) Neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser,     Thr) -   xii) Hydrophilic, acidic amino acids (Gln, Asn, Glu, Asp), and -   xiii) Hydrophobic amino acids (Leu, Ile, Val)

Accordingly, a homologue or a fragment thereof according to the invention may comprise, within the same homologue of the sequence or fragments thereof, or among different variants of the sequence or fragments thereof, at least one substitution, such as a plurality of substitutions introduced independently of one another.

It is clear from the above outline that the same homologue or fragment thereof may comprise more than one conservative amino acid substitution from more than one group of conservative amino acids as defined herein above.

The addition or deletion of at least one amino acid may be an addition or deletion of from preferably 2 to 250 amino acids, such as from 10 to 20 amino acids, for example from 20 to 30 amino acids, such as from 40 to 50 amino acids. However, additions or deletions of more than 50 amino acids, such as additions from 50 to 100 amino acids, addition of 100 to 150 amino acids, addition of 150-250 amino acids, are also comprised within the present invention. The deletion and/or the addition may—independently of one another—be a deletion and/or an addition within a sequence and/or at the end of a sequence.

The polypeptide fragments according to the present invention, including any functional equivalents thereof, may in one embodiment comprise less than 250 amino acid residues, such as less than 240 amino acid residues, for example less than 225 amino acid residues, such as less than 200 amino acid residues, for example less than 180 amino acid residues, such as less than 160 amino acid residues, for example less than 150 amino acid residues, such as less than 140 amino acid residues, for example less than 130 amino acid residues, such as less than 120 amino acid residues, for example less than 110 amino acid residues, such as less than 100 amino acid residues, for example less than 90 amino acid residues, such as less than 85 amino acid residues, for example less than 80 amino acid residues, such as less than 75 amino acid residues, for example less than 70 amino acid residues, such as less than 65 amino acid residues, for example less than 60 amino acid residues, such as less than 55 amino acid residues, for example less than 50 amino acid residues.

The homology between amino acid sequences may be calculated using well known scoring matrices such as any one of BLOSUM 30, BLOSUM 40, BLOSUM 45, BLOSUM 50, BLOSUM 55, BLOSUM 60, BLOSUM 62, BLOSUM 65, BLOSUM 70, BLOSUM 75, BLOSUM 80, BLOSUM 85, and BLOSUM 90.

In addition to conservative substitutions introduced into any position of a preferred predetermined sequence, or a fragment thereof, it may also be desirable to introduce non-conservative substitutions in any one or more positions of such a sequence.

A non-conservative substitution leading to the formation of a functionally equivalent fragment of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. 19 and 20 would for example i) differ substantially in polarity, for example a residue with a non-polar side chain (Ala, Leu, Pro, Trp, Val, Ile, Leu, Phe or Met) substituted for a residue with a polar side chain such as Gly, Ser, Thr, Cys, Tyr, Asn, or Gln or a charged amino acid such as Asp, Glu, Arg, or Lys, or substituting a charged or a polar residue for a non-polar one; and/or ii) differ substantially in its effect on polypeptide backbone orientation such as substitution of or for Pro or Gly by another residue; and/or iii) differ substantially in electric charge, for example substitution of a negatively charged residue such as Glu or Asp for a positively charged residue such as Lys, His or Arg (and vice versa); and/or iv) differ substantially in steric bulk, for example substitution of a bulky residue such as His, Trp, Phe or Tyr for one having a minor side chain, e.g. Ala, Gly or Ser (and vice versa).

Homologues obtained by substitution of amino acids may in one preferred embodiment be made based upon the hydrophobicity and hydrophilicity values and the relative similarity of the amino acid side-chain substituents, including charge, size, and the like. Exemplary amino acid substitutions which take several of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.

In a further embodiment the present invention relates to functional variants comprising substituted amino acids having hydrophilic values or hydropathic indices that are within +/−4.9, for example within +/−4.7, such as within +/−4.5, for example within +/−4.3, such as within +/−4.1, for example within +/−3.9, such as within +/−3.7, for example within +/−3.5, such as within +/−3.3, for example within +/−3.1, such as within +/−2.9, for example within +/−2.7, such as within +/−2.5, for example within +/−2.3, such as within +/−2.1, for example within +/−2.0, such as within +/−1.8, for example within +/−1.6, such as within +/−1.5, for example within +/−1.4, such as within +/−1.3 for example within +/−1.2, such as within +/−1.1, for example within +/−1.0, such as within +/−0.9, for example within +/−0.8, such as within +/−0.7, for example within +/−0.6, such as within +/−0.5, for example within +/−0.4, such as within +/−0.3, for example within +/−0.25, such as within +/−0.2 of the value of the amino acid it has substituted.

The importance of the hydrophilic and hydropathic amino acid indices in conferring interactive biologic function on a protein is well understood in the art (Kyte & Doolittle, 1982 and Hopp, U.S. Pat. No. 4,554,101, each incorporated herein by reference).

The amino acid hydropathic index values as used herein are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (−0.4); threonine (−0.7); serine (−0.8); tryptophan (−0.9); tyrosine (−1.3); proline (−1.6); histidine (−3.2); glutamate (−3.5); glutamine (−3.5); aspartate (−3.5); asparagine (−3.5); lysine (−3.9); and arginine (−4.5) (Kyte & Doolittle, 1982).

The amino acid hydrophilicity values are: arginine (+3.0); lysine (+3.0); aspartate (+3.0.+−0.1); glutamate (+3.0.+−0.1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (−0.4); proline (−0.5.+−0.1); alanine (−0.5); histidine (−0.5); cysteine (−1.0); methionine (−1.3); valine (−1.5); leucine (−1.8); isoleucine (−1.8); tyrosine (−2.3); phenylalanine (−2.5); tryptophan (−3.4) (U.S. Pat. No. 4,554,101).

Method of Growing RSK/MSK Crystal

Growing of a crystal as defined herein above may according to the invention be performed by any suitable method known in the art, such as vapour diffusions methods and/or hanging drops systems known by the person skilled in the art.

As described above the crystal may contain one or more ligands, such as DMF and DMF analogues conveniently added after the purification process and before crystallization is initiated. Alternatively crystals may be submerged in a solution comprising the ligand of choice subsequent to crystallization. Alternatively a composition comprising the ligand may be added to the hanging or sitting drop of the vapour diffusion setup, prior to or subsequent to formation of the crystal.

An aspect of the invention relates to a method of growing a crystal comprising a ribosomal S6 kinase (RSK) or a mitogen- and stress-activated protein kinase (MSK) polypeptide. Such method includes the steps of obtaining a protein composition of sufficient quality for growing of a crystal and growing of the a RSK/MSK crystals. As described herein, both steps can be modulated to optimise the outcome.

Initiation of crystal formation can be nucleated by lowering the solubility of the RSK/MSK. According to the invention PEG is included in the crystallizations environment. PEG is preferably selected from the group of PEGs comprising: PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 5000, PEG 6000, PEG 7000 and PEG 8000.

An aspect of the invention relates to a method for growing a crystal comprising an RSK/MSK and a ligand comprising the steps of:

-   -   a. obtaining a composition comprising an RSK/MSK,     -   b. contacting the composition of a) with a ligand of choice thus         obtaining a protein:ligand complex composition     -   c. subjecting the complex composition of b) to crystallizations         environment including PEG 3350 and     -   d. obtaining a crystal comprising an RSK/MSK.

The crystallization environment may according to the invention be obtained by mixing a composition comprising an RSK/MSK with a precipitating solution comprising PEG3350. As mentioned above any suitable method of growing crystals may be used, although vapour diffusion from hanging drops is preferred.

In an embodiment the invention relates to a method of growing a crystal comprising a RSK/MSK, comprising the steps of:

-   -   a. obtaining a composition comprising a RSK/MSK,     -   b. mixing said composition comprising a RSK/MSK with a         precipitating solution comprising PEG3350,     -   c. growing RSK/MSK crystals by vapour diffusion from hanging         drops     -   d. obtaining crystals comprising RSK/MSK.

The precipitating solution used in Example 5 herein comprises 0.1 M Bis-Tris pH 6.5 and 25% (w/v) polyethylene glycol (PEG) 3350), which is the most preferred precipitating solution according to the present invention.

In one aspect the present invention concerns a method for growing a crystal as defined herein above, comprising the steps of:

-   a) obtaining a composition comprising 5 to 15 mg/mL of a polypeptide     selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6,     7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 or a fragment     or variant thereof, in a suitable buffer -   b) contacting the composition of a) with a ligand as defined herein     above, -   c) allowing time for formation of a protein-ligand complex in     solution, -   d) mixing the solution comprising the protein-ligand complex of c)     with a reservoir solution comprising a precipitant and a buffer, -   e) incubating a drop of the mixture of d) under vapour diffusion     conditions versus the reservoir solution, -   f) obtaining crystals of the protein-ligand complex.

In one embodiment the reservoir solution is an aqueous solution of either 0.1 M Bis-Tris pH 6.5, HEPES pH=7.0 or TrisHCl pH=8.5 and 25% (w/v) polyethylene glycol (PEG) 3350.

In one embodiment of the method, equal volumes of protein-ligand complex and reservoir solution are mixed in step d) above. The equal volumes may e.g. be 0.2-4 μl.

In one embodiment the method is performed at room temperature (18-25° C.).

In another embodiment the method is performed at about 4° C.

The inventors have observed that crystals of improved quality are obtained when the method of growing a crystal further comprises an additive such as an aqueous solution of 0.01-1 M NaF, preferably 0.05 M NaF.

In one embodiment, methionine residues of the polypeptide to be crystallized are replaced by seleno-methionine by conventional molecular biological methods known by those of skill in the art.

In one embodiment the method according to the present invention further comprises the steps of:

-   -   a) isolating an initial precipitate and     -   b) growing crystals from the precipitate by vapour diffusion         from hanging or sitting drops.

Use of Crystal

Provided that crystals of sufficient quality have been obtained, the crystals may according to the invention be used for X-ray diffraction experiments.

An aspect of the invention relates to the use of RSK/MSK crystals for determination of the three dimensional structure of said RSK/MSK polypeptide.

Before data collection crystals may be if deemed necessary be treated by standard methods for phasing, known in the art. However, in a preferred embodiment phasing is performed by molecular replacement techniques.

Crystals are according to the invention preferably dehydrated by conventional methods such as using cryo-protectants such as sucrose, glycerol and salt etc. Dehydration may be performed by increasing the concentration of the precipitating agent, such as PEG3350 or by controlled humidity around the crystal.

The crystals are mounted in nylon loops and flashed cooled in liquid. Excess mother liquor of the crystallisation mixture can be removed prior to flash cooling by gently touching a glass cover slip with the edge of the loop,

Data collection and data processing can be performed by any suitable systems know by the person skilled in the art. Data may be collected at 100 K on the end stations at e.g. Deutsches Elektronen-Synchrotron (DESY) in Hamburg or the Swiss Light Source SLS in Villigen. Processing may be performed using XDS. Data processing is further described in the examples.

Method Using Information Derived from a Three Dimensional Structure of an RSK/MSK

Those of skill in the art will understand that a set of structure coordinates for a protein or protein complex or a portion thereof, is a relative set of points that define a shape in three dimensions. Thus, it is possible that an entirely different set of coordinates could define a similar or identical shape. The variations in coordinates may be generated by mathematical manipulations of the structure coordinates. For example, the structure coordinates set forth in table 3 could be manipulated by crystallographic permutations of the structure coordinates, fractionalization or matrix operations to sets of the structure coordinates or any combination of the above.

Coordinates Stored on Machine Readable Storage Medium

In a further aspect the invention provide a computer-readable data storage medium comprising a data storage material encoded with the structure coordinates, or at least a portion of the structure coordinates set forth in table 3. Examples of such computer readable data storage media are well known to those skilled in the art and include, for example CD-ROM and hard disks such as portable hard disks. Thus, in accordance with the present invention, the structure coordinates of a RSK/MSK, and portions thereof can be stored in a machine-readable storage medium. Such data may be used for a variety of purposes, such as drug discovery and X-ray crystallographic analysis of protein crystal.

The storage medium may be local to a computer as described above, or the storage medium may be located in a net-worked storage medium including the internet, to which remote accessibility is possible.

Three-dimensional structures provide information regarding the spatial localization of the peptide backbone and the side chains of the amino acid residues of the protein complex. Such information cannot be derived from the primary amino acid sequence or from the knowledge of the secondary structure of the protein. The level of order of the crystal determines the level of details that can be obtained. The quality of a three dimensional structure is evaluated by the resolution obtained, which is an expression for the minimum spacing observed in diffraction. As mentioned above the application relates to crystals of high quality e.g. crystals with a resolution of better than 6 Å preferably better than 4 Å, most preferably around 2 Å or better, which is required to have a sufficiently detailed model for selecting potential binding molecules e.g. modulators such as inhibitors of kinase activity.

In order to employ virtual screening (by database docking programs such as Dock, FlexX, Gold, Glide and Maestro programs from Schrödinger, Vina Autodock and Molegro virtual docker) detailed structural information of the molecule is necessary.

Identification of Modulators

According to the invention various strategies can be followed to identify and generate modulators of RSK/MSK based on the structural information described herein. Modulators according to the invention may stimulate or inhibit the overall kinase activity of the RSK/MSK.

Potential modulators are molecules that can bind to the binding site the of same binding site of RSK/MSK as DMF. These modulators can be identified trough virtual screening of chemical databases. Virtual screening are performed with different database docking programs (for instance Dock, FlexX, Gold, Flo, Fred, Glide, LigFit, MOE or MVP, but not limited to these) and used with different scoring functions (e.g. Warren et. al., 2005; Jain, 2006; Seifert et al., 2007). The scoring functions may include, but are not limited to force-field scoring functions (affinities estimated by summing Van der Waals and electrostatic interactions of all atoms in the complex between the RSK/MSK and the ligand), empirical scoring functions (counting the number of various interactions, for instance number of hydrogen bonds, hydrophobic-hydrophobic contacts and hydrophilic-hydrophobic contacts, between the RSK/MSK and the ligand), and knowledge based scoring functions (with basis on statistical findings of intermolecular contacts involving certain types of atoms or functional groups). Scoring functions involving terms from any of the two of the mentioned scoring functions may also be combined into a single function used in database virtual screening of chemical libraries.

Identified potential modulators are confirmed by in vitro and in vivo experiments before further developments. The binding of modulators may further be confirmed by x-ray experiments. Even when modulating activity is confirmed further drug development may be required before a compound suitable as a drug is identified.

As seen from the above and the examples the three-dimensional structure described herein has identified a binding site for DMF in RSK2 and specified the amino acid residues involved in phosphorylation. Based on this knowledge potential modulators of a RSK/MSK can be identified. It is preferred that the structure used is the atomic coordinates presented in table 3, but a structure that deviates from the tree-dimensional structures as presented in table 3 by a root mean square deviation over protein backbone atoms of not more than 3 Å may like wise used. It is preferred that the deviate is less than 2 Å, more preferably less than 1 Å.

Such methods are preferable performed using computers, whereby the atomic coordinates are introduced into the computer, allowing generation of a model on the computer screen which allows visual selection of binding molecules.

Methods of Selecting or Identifying Potential Modulators

Preferably, potential modulators such as inhibitors are selected by their potential of binding to the binding pocket of the RSK/MSK. Compounds which bind to this pocket or region of the structure can be expected to interfere with the function of the kinase and is thus a potential modulator of the kinase. When selecting a potential modulator by computer modelling, the 3D structure of the kinase is loaded from a data storage device into a computer memory and may be displayed (generated) on a computer screen using a suitable computer program. Preferably, only a subset of interest of the coordinates of the whole structure of the kinase is loaded in the computer memory or displayed on the computer screen. This subset of interest may comprise the coordinates of the binding pocket. This subset may be called a criteria data set; this subset of atoms may be used for designing a modulator such as an inhibitor.

In one aspect the present invention relates to a computer-based method for rational drug design which comprises:

-   a) providing the atomic coordinates of the polypeptide as defined by     the coordinates of a table selected from table 3; -   b) providing the structure of a candidate inhibitor molecule; and -   c) fitting the structure of candidate inhibitor molecule to the     atomic coordinates of the polypeptide of said table.

In another aspect the invention concerns a computer-based method for identifying a potential inhibitor of the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 comprising the steps of:

-   a) employing a three-dimensional structure of the polypeptide, the     three-dimensional structure being defined by atomic coordinate data     according to table 3; and -   b) identifying the potential inhibitor by designing or selecting a     compound for interaction with the active site.

In one embodiment the method further comprises:

-   a) obtaining or synthesizing the potential inhibitor; -   b) contacting the potential inhibitor with the polypeptide selected     from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9,     10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 to determine the     ability of said inhibitor to interact with said polypeptide.

In another embodiment the method further comprises:

-   a) obtaining or synthesising said potential inhibitor; -   b) forming a complex of said polypeptide selected from the group     consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,     14, 15, 16, 17, 18, 19 and 20; and said potential inhibitor; and -   c) analysing said complex by X-ray crystallography to determine the     ability of said potential inhibitor to interact with said     polypeptide.

In an a further aspect the potential modulators such as inhibitors are identified using a computer, wherein the computer comprise programs and processor capable of utilizing the three dimensional structure information for selecting potential inhibitors bases on a criteria data set which defines target regions of the RSK/MSK. Data bases of potential inhibitors, such as data bases of low molecular weight organic and/or inorganic chemical structures can be stored in the computer, e.g. in a storage system and used by the processor of the computer to identify potential inhibitors which in a region are structurally complementary to the criteria data set and being free of steric interference with the RSK/MSK. Modulators being, in a region, complementary to the criteria data set, can be interpreted as inhibitors capable of accommodating a three-dimensional cavity defined by the criteria data set with out interfering with the structure of the target. Complementary indicates that the RSK/MSK and the modulator interact with each other in an energy favourable way minimizing the availability of polar and charged residues (see below). The storage medium may be local to the computer as described above, or the storage medium may be remote such as a net-worked storage medium including the internet.

The low molecular weight organic chemical structures may include structures such as lipids, nucleic acids, peptides, proteins, antibodies and saccharides.

A computer-assisted method for identifying potential modulators of a RSK/MSK using a programmed computer comprising a processor, a data storage system, a data input devise and a data output device, comprising the following steps:

-   -   a. inputting into the programmed computer through said input         device data comprising:         -   atomic coordinates of a subset of the atoms of said RSK/MSK,             thereby generating a criteria data set;         -   wherein said atomic coordinates atomic coordinates are             selected from the tree-dimensional structure presented in             table 3 or atomic coordinates selected from a             three-dimensional structure that deviates from the             tree-dimensional structure presented in table 3 by a root             mean square deviation over protein backbone atoms of not             more than 3 Å,     -   b. comparing, using said processor, the criteria data set to a         computer data base of low-molecular weight organic chemical         structures stored in the data storage system; and     -   c. selecting from said data base, using computer methods, a         chemical structure having a portion that is structurally         complementary to the criteria data set and being free of steric         interference with the RSK/MSK.

In one aspect the present invention comprises a computer readable media with either (a) atomic coordinate data according to table 3 recorded thereon, said data defining the three-dimensional structure of the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, at least one atom or at least one sub-domain thereof, or (b) structure factor data for the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 recorded thereon, the structure factor data being derivable from the atomic coordinate data of table 3.

In another aspect the invention concerns a computer-readable data storage medium comprising a data storage material encoded with at least a portion of the structure coordinates set forth in table 3.

In yet another aspect the invention concerns a method for identifying a ligand capable of binding to the binding site of SEQ ID NO. 1 (C-terminal domain of murine RSK2), said method comprising the steps of:

-   -   a) generating the spatial structure of the binding site on a         computer screen using atomic coordinates as presented in table 3         or atomic coordinates selected from a three-dimensional         structure that deviates from the three-dimensional structure         presented in table 3 by a root mean square deviation over         protein backbone atoms of not more than 3 Å,     -   b) generating potential ligands with their spatial structure on         the computer screen, and     -   c) selecting ligands that can bind to at least 1 amino acid         residue of the set of binding interaction sites without steric         interference.

In one aspect the invention relates to a computer-assisted method for identifying a ligand of a polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, using a programmed computer comprising a processor, a data storage system, a data input device and a data output device, comprising the following steps:

-   -   a) inputting into the programmed computer through said input         device data comprising:         -   atomic coordinates of a subset of the atoms of said             polypeptide, thereby generating a criteria data set;         -   wherein said atomic coordinates are selected from the             three-dimensional structure presented in table 3 or atomic             coordinates selected from a three-dimensional structure that             deviates from the three-dimensional structure presented             table 3 by a root mean square deviation over protein             backbone atoms of not more than 3 Å,     -   b) comparing, using said processor, the criteria data set to a         computer data base of low-molecular weight organic chemical         structures and peptide fragments stored in the data storage         system; and     -   c) selecting from said database, using computer methods, a         chemical structure having a portion that is structurally         complementary to the criteria data set and being free of steric         interference with the polypeptide selected from the group         consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,         13, 14, 15, 16, 17, 18, 19 and 20.

In yet another aspect the invention relates to a method for identifying a ligand, said method comprising the steps of:

-   -   a) selecting a potential ligand using atomic coordinates in         conjunction with computer modelling, wherein said atomic         coordinates are the atomic coordinates presented in table 3 or         wherein the atomic coordinates are selected from a         three-dimensional structure that deviates from the         three-dimensional structure presented in any of table 3 by a         root mean square deviation over protein backbone atoms of not         more than 3 Å, by docking potential ligands into a set of         binding interaction sites the binding site of said polypeptide         selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5,         6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, said         binding interaction generated by computer modelling and         selecting a potential ligand capable of binding to at least one         amino acid in said set of binding interaction sites of said         polypeptide selected from the group consisting of SEQ ID NO. 1,         2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19         and 20,     -   b) providing said potential ligand and said polypeptide,     -   c) contacting the potential ligand with said polypeptide and     -   d) detecting binding of said polypeptide by the potential         ligand.

In one embodiment the atomic coordinates are determined to a resolution of at least 5 Å, preferably at least 4 Å, more preferably at least 3 Å, more preferably at least 2 Å, more preferably at least 1.5 Å.

In one embodiment the potential inhibitor is selected from the group consisting of non-hydrolyzable peptides and peptide analogues, organic compounds and inorganic compounds.

A potential inhibitor may be designed de novo in conjunction with computer modelling. Models of chemical structures or molecule fragments may be generated on a computer screen using information derived from known low-molecular weight organic chemical structures stored in a computer data base or are built using the general knowledge of an organic chemist regarding bonding types, conformations etc. Suitable computer programs may aid in this process in order to build chemical structures of realistic geometries. Chemical structures or molecule fragments may be selected and/or used to construct a potential inhibitor such that favourable interactions to said subset or criteria data set become possible. The more favourable interactions become possible, the stronger the potential inhibitor will bind to the RSK/MSK. Preferably, favourable interactions to at least one amino acid residues should become possible. Such favourable interactions may occur with any atom of the amino acid residue e.g. atoms of the peptide back-bone or/and atoms of the side chains.

Favourable interactions are any non-covalent attractive forces which may exist between chemical structures such as hydrophobic or van-der-Waals interactions and polar interactions such as hydrogen bonding, salt-bridges etc. Unfavourable interactions such as hydrophobic-hydrophilic interactions should be avoided but may be accepted if they are weaker than the sum of the attractive forces. Steric interference such as clashes or overlaps of portions of the inhibitor being selected or constructed with protein moieties will prevent binding unless resolvable by conformational changes. The binding strength of a potential inhibitor thus created may be assessed by comparing favourable and unfavourable interactions on the computer screen or by using computational methods implemented in commercial computer programs.

Conformational freedom of the potential inhibitor and amino acid side chains of the RSK/MSK should be taken into account. Accessible conformations of a potential inhibitor may be determined using known rules of molecular geometry, notably torsion angles, or computationally using computer programs having implemented procedures of molecular mechanics and/or dynamics or quantum mechanics or combinations thereof.

A potential inhibitor is at least partially complementary to at least a portion of the active site of the RSK/MSK in terms of shape and in terms of hydrophilic or hydrophobic properties.

Databases of chemical structures (e. g. Cambridge structural database or from Chemical Abstracts Service; for a review see: Rusinko (1993) Chem. Des. Auto. News 8, 44-47) may be used to varying extents. In a totally automatic embodiment, all structures in a data base may be compared to the active site or to the binding pockets of the RSK/MSK for complementarity and lack of steric interference computationally using the processor of the computer and a suitable computer program. In this case, computer modelling which comprises manual user interaction at a computer screen may not be necessary. Alternatively, molecular fragments may be selected from a data base and assembled or constructed on a computer screen e. g. manually. Also, the ratio of automation to manual interaction by a person skilled in the art in the process of selecting may vary a lot. As computer programs for drug design and docking of molecules to each other become better, the need for manual interaction decreases.

A preferred approach of selecting or identifying potential inhibitors of RSK/MSKs makes use of the structure of the murine RSK2 of this invention. Analogously to the principles of drug design and computer modelling outlined above, chemical structures or fragments thereof may be selected or constructed based on non-covalent interactions with the potential inhibitor with the binding pocket of the RSK/MSK.

Programs usable for computer modelling include Quanta (Molecular Simulations, Inc.) and Sibyl (Tripos Associates). Other useful programs are Autodock (Scripps Research Institute, La Jolla, described in Goodsell and Olsen (1990) Proteins: Structure, Function and Genetics, 8, 195-201), Dock (University of California, San Francisco, described in: Kuntz et al. (1982) J. Mol. Biol. 161, 269-288.

Methods for Verification of Inhibitors

The activity of identified modulators may be verified by established methods. In vitro verification may be demonstrated by studying binding and inhibition of kinase activity. In vitro verification may be shown by administration of potential inhibitors to cell cultures such as COS cells. In vivo experiments may be performed on mice. The binding is further confirmed by X-ray studies. Such methods are known in the art and an example is described in examples 7-9.

The potential inhibitors can be synthesized according to the methods of organic chemistry. Preferably, compounds from a database have been selected without remodelling, and their synthesis may already be known.

In any event, the synthetic effort needed to find an inhibitor is greatly reduced by the achievements of this invention due to the pre-selection of promising inhibitors by the above methods. Binding of a potential modulator may be determined after contacting the potential inhibitor with the RSK/MSK. This may be done crystallographically by soaking a crystal of the RSK/MSK with the potential inhibitor or by co-crystallisation and determining the crystal structure of the complex. Preferably, binding may be measured in solution according to methods known in the art. More preferably, inhibition of the catalytic activity of the RSK/MSK by the inhibitor is determined e.g. using the assays described in the examples section.

EXAMPLES Example 1 Sequences

SEQ ID NO. 1: Murine C-terminal domain of RSK2 used for crystallization >RSK2_crystallization GQTVGVHSIVQQLHRNSIQFTDGYEVKEDIGVGSYSVCKRCIHKATNMEFAVKIIDKSKRDPTEEIE ILLRYGQHPNIITLKDVYDDGKYVYVVTELMKGGELLDKILRQKFFSEREASAVLFTITKTVEYLHA QGVVHRDLKPSNILYVDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAAC DIWSLGVLLYTMLTGYTPFANGPDDTPEEILARIGSGKFSLSGGYWNSVSDTAKDLVSKMLHVDPHQ RLTAALVLRHPWIVHWDQLPQYQLNRQDAPHLVKGAMAATYSALNRNQSPVLEPVGRSTLAQRRGIK KITSTAL SEQ ID NO. 2: Murine C-terminal domain of RSK2 used for crystallization, without N-terminal G from TEV protease cleavage site >RSK2_crystallization_wo_G QTVGVHSIVQQLHRNSIQFTDGYEVKEDIGVGSYSVCKRCIHKATNMEFAVKIIDKSKRDPTEEIEI LLRYGQHPNIITLKDVYDDGKYVYVVTELMKGGELLDKILRQKFFSEREASAVLFTITKTVEYLHAQ GVVHRDLKPSNILYVDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAACD IWSLGVLLYTMLTGYTPFANGPDDTPEEILARIGSGKFSLSGGYWNSVSDTAKDLVSKMLHVDPHQR LTAALVLRHPWIVHWDQLPQYQLNRQDAPHLVKGAMAATYSALNRNQSPVLEPVGRSTLAQRRGIKK ITSTAL SEQ ID NO. 3: Human RSK1 >RSK1_human(Q15418) MPLAQLKEPWPLMELVPLDPENGQTSGEEAGLQPSKDEGVLKEISITHHVKAGSEKADPSHFELLKV LGQGSFGKVFLVRKVTRPDSGHLYAMKVLKKATLKVRDRVRTKMERDILADVNHPFVVKLHYAFQTE GKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALGLDHLHSLGIIYRDLKPENILLDEEGHI KLTDFGLSKEAIDHEKKAYSFCGTVEYMAPEVVNRQGHSHSADWWSYGVLMFEMLTGSLPFQGKDRK ETMTLILKAKLGMPQFLSTEAQSLLRALFKRNPANRLGSGPDGAEEIKRHVFYSTIDWNKLYRREIK PPFKPAVAQPDDTFYFDTEFTSRTPKDSPGIPPSAGAHQLFRGFSFVATGLMEDDGKPRAPQAPLHS VVQQLHGKNLVFSDGYVVKETIGVGSYSECKRCVHKATNMEYAVKVIDKSKRDPSEEIEILLRYGQH PNIITLKDVYDDGKHVYLVTELMRGGELLDKILRQKFFSEREASFVLHTIGKTVEYLHSQGVVHRDL KPSNILYVDESGNPECLRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDEGCDIWSLGIL LYTMLAGYTPFANGPSDTPEEILTRIGSGKFTLSGGNWNTVSETAKDLVSKMLHVDPHQRLTAKQVL QHPWVTQKDKLPQSQLSHQDLQLVKGAMAATYSALNSSKPTPQLKPIESSILAQRRVRKLPSTTL SEQ ID NO. 4: Human RSK2 >RSK2_human(P51812) MPLAQLADPWQKMAVESPSDSAENGQQIMDEPMGEEEINPQTEEVSIKEIAITHHVKEGHEKADPSQ FELLKVLGQGSFGKVFLVKKISGSDARQLYAMKVLKKATLKVRDRVRTKMERDILVEVNHPFIVKLH YAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALALDHLHSLGIIYRDLKPENILL DEEGHIKLTDFGLSKESIDHEKKAYSFCGTVEYMAPEVVNRRGHTQSADWWSFGVLMFEMLTGTLPF QGKDRKETMTMILKAKLGMPQFLSPEAQSLLRMLFKRNPANRLGAGPDGVEEIKRHSFFSTIDWNKL YRREIHPPFKPATGRPEDTFYFDPEFTAKTPKDSPGIPPSANAHQLFRGFSFVAITSDDESQAMQTV GVHSIVQQLHRNSIQFTDGYEVKEDIGVGSYSVCKRCIHKATNMEFAVKIIDKSKRDPTEEIEILLR YGQHPNIITLKDVYDDGKYVYVVTELMKGGELLDKILRQKFFSEREASAVLFTITKTVEYLHAQGVV HRDLKPSNILYVDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAACDIWS LGVLLYTMLTGYTPFANGPDDTPEEILARIGSGKFSLSGGYWNSVSDTAKDLVSKMLHVDPHQRLTA ALVLRHPWIVHWDQLPQYQLNRQDAPHLVKGAMAATYSALNRNQSPVLEPVGRSTLAQRRGIKKITS TAL SEQ ID NO. 5: Human RSK3 >RSK3_human(Q15349) MDLSMKKFAVRRFFSVYLRRKSRSKSSSLSRLEEEGVVKEIDISHHVKEGFEKADPSQFELLKVLGQ GSYGKVFLVRKVKGSDAGQLYAMKVLKKATLKVRDRVRSKMERDILAEVNHPFIVKLHYAFQTEGKL YLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALALDHLHSLGIIYRDLKPENILLDEEGHIKIT DFGLSKEAIDHDKRAYSFCGTIEYMAPEVVNRRGHTQSADVWVSFGVLMFEMLTGSLPFQGKDRKET MALILKAKLGMPQFLSGEAQSLLRALFKRNPCNRLGAGIDGVEEIKRHPFFVTIDWNTLYRKEIKPP FKPAVGRPEDTFHFDPEFTARTPTDSPGVPPSANAHHLFRGFSFVASSLIQEPSQQDLHKVPVHPIV QQLHGNNIHFTDGYEIKEDIGVGSYSVCKRCVHKATDTEYAVKIIDKSKRDPSEEIEILLRYGQHPN IITLKDVYDDGKFVYLVMELMRGGELLDRILRQRYFSEREASDVLCTITKTMDYLHSQGVVHRDLKP SNILYRDESGSPESIRVCDFGFAKQLRAGNGLLMTPCYTANFVAPEVLKRQGYDAACDIWSLGILLY TMLAGFTPFANGPDDTPEEILARIGSGKYALSGGNWDSISDAAKDVVSKMLHVDPHQRLTAMQVLKH PWVVNREYLSPNQLSRQDVHLVKGAMAATYFALNRTPQAPRLEPVLSSNLAQRRGMKRLTSTRL SEQ ID NO. 6: Human RSK4 >RSK4_human(Q9UK32) MLPFAPQDEPWDREMEVFSGGGASSGEVNGLKMVDEPMEEGEADSCHDEGVVKEIPITHHVKEGYEK ADPAQFELLKVLGQGSFGKVFLVRKKTGPDAGQLYAMKVLKKASLKVRDRVRTKMERDILVEVNHPF IVKLHYAFQTEGKLYLILDFLRGGDVFTRLSKEVLFTEEDVKFYLAELALALDHLHQLGIVYRDLKP ENILLDEIGHIKLTDFGLSKESVDQEKKAYSFCGTVEYMAPEVVNRRGHSQSADWWSYGVLMFEMLT GTLPFQGKDRNETMNMILKAKLGMPQFLSAEAQSLLRMLFKRNPANRLGSEGVEEIKRHLFFANIDW DKLYKREVQPPFKPASGKPDDTFCFDPEFTAKTPKDSPGLPASANAHQLFKGFSFVATSIAEEYKIT PITSANVLPIVQINGNAAQFGEVYELKEDIGVGSYSVCKRCIHATTNMEFAVKIIDKSKRDPSEEIE ILMRYGQHPNIITLKDVFDDGRYVYLVTDLMKGGELLDRILKQKCFSEREASDILYVISKTVDYLHC QGVVHRDLKPSNILYMDESASADSIRICDFGFAKQLRGENGLLLTPCYTANFVAPEVLMQQGYDAAC DIWSLGVLFYTMLAGYTPFANGPNDTPEEILLRIGNGKFSLSGGNWDNISDGAKDLLSHMLHMDPHQ RYTAEQILKHSWITHRDQLPNDQPKRNDVSHVVKGAMVATYSALTHKTFQPVLEPVAASSLAQRRSM KKRTSTGL SEQ ID NO. 7: Human MSK1 >MSK1_human(O75582) MEEEGGSSGGAAGTSADGGDGGEQLLTVKHELRTANLTGHAEKVGIENFELLKVLGTGAYGKVFLVR KISGHDTGKLYAMKVLKKATIVQKAKTTEHTRTERQVLEHIRQSPFLVTLHYAFQTETKLHLILDYI NGGELFTHLSQRERFTEHEVQIYVGEIVLALEHLHKLGIIYRDIKLENILLDSNGHVVLTDFGLSKE FVADETERAYSFCGTIEYMAPDIVRGGDSGHDKAVDWWSLGVLMYELLTGASPFTVDGEKNSQAEIS RRILKSEPPYPQEMSALAKDLIQRLLMKDPKKRLGCGPRDADEIKEHLFFQKINWDDLAAKKVPAPF KPVIRDELDVSNFAEEFTEMDPTYSPAALPQSSEKLFQGYSFVAPSILFKRNAAVIDPLQFHMGVER PGVTNVARSAMMKDSPFYQHYDLDLKDKPLGEGSFSICRKCVHKKSNQAFAVKIISKRMEANTQKEI TALKLCEGHPNIVKLHEVFHDQLHTFLVMELLNGGELFERIKKKKHFSETEASYIMRKLVSAVSHMH DVGVVHRDLKPENLLFTDENDNLEIKIIDFGFARLKPPDNQPLKTPCFTLHYAAPELLNQNGYDESC DLWSLGVILYTMLSGQVPFQSHDRSLTCTSAVEIMKKIKKGDFSFEGEAWKNVSQEAKDLIQGLLTV DPNKRLKMSGLRYNEWLQDGSQLSSNPLMTPDILGSSGAAVHTCVKATFHAFNKYKREGFCLQNVDK APLAKRRKMKKTSTSTETRSSSSESSHSSSSHSHGKTTPTKTLQPSNPADSNNPETLFQFSDSVA SEQ ID NO. 8: Human MSK2 >MSK2_human(O75676) MGDEDDDESCAVELRITEANLTGHEEKVSVENFELLKVLGTGAYGKVFLVRKAGGHDAGKLYAMKVL RKAALVQRAKTQEHTRTERSVLELVRQAPFLVTLHYAFQTDAKLHLILDYVSGGEMFTHLYQRQYFK EAEVRVYGGEIVLALEHLHKLGIIYRDLKLENVLLDSEGHIVLTDFGLSKEFLTEEKERTFSFCGTI EYMAPEIIRSKTGHGKAVDWWSLGILLFELLTGASPFTLEGERNTQAEVSRRILKCSPPFPPRIGPV AQDLLQRLLCKDPKKRLGAGPQGAQEVRNHPFFQGLDWVALAARKIPAPFRPQIRSELDVGNFAEEF TRLEPVYSPPGSPPPGDPRIFQGYSFVAPSILFDHNNAVMTDGLEAPGAGDRPGRAAVARSAMMQDS PFFQQYELDLREPALGQGSFSVCRRCRQRQSGQEFAVKILSRRLEANTQREVAALRLCQSHPNVVNL HEVHHDQLHTYLVLELLRGGELLEHIRKKRHFSESEASQILRSLVSAVSFMHEEAGVVHRDLKPENI LYADDTPGAPVKIIDFGFARLRPQSPGVPMQTPCFTLQYAAPELLAQQGYDESCDLWSLGVILYMML SGQVPFQGASGQGGQSQAAEIMCKIREGRFSLDGEAWQGVSEEAKELVRGLLTVDPAKRLKLEGLRG SSWLQDGSARSSPPLRTPDVLESSGPAVRSGLNATFMAFNRGKREGFFLKSVENAPLAKRRKQKLRS ATASRRGSPAPANPGRAPVASKGAPRRANGPLPPS SEQ ID NO. 9: Mouse RSK1 >RSK1_mouse(P18653) MPLAQLKEPWPLMELVPLDPENGQTSGEEAGLQPSKDEAILKEISITHHVKAGSEKADPSQFELLKV LGQGSFGKVFLVRKVTRPDSGHLYAMKVLKKATLKVRDRVRTKMERDILADVNHPFVVKLHYAFQTE GKLYLILFLRGGDLFTRLSKEVMFTEEDVKFYLAELALGLDHLHSLGIIYRDLKPENILLDEEGHIK LTDFGLSKEAIDHEKKAYSFCGTVEYMAPEVVNRQGHTHSADWWSYGVLMGKDRKETMTLILKAKLG MPQFLSTEAQSLLRALFKRNPANRLGSGPDGAEEIKRHIFYSTIDWNKLYRREIKPPFKPAVAQPDD TFYFDTEFTSRTPRDSPGIPPSAGAHQLFRGFSFVATGLMEDDGKPRTTQAPLHSVVQQLHGKNLVF SDGYVVKETIGVGSYSVCKRCVHKATNMEYAVKVIDKSKRDPSEEIEILLRYGQHPNIITLKDVYDD GKHVYLVTELMRGGELLDKILRQKFFSEREASFVLHTISKTVEYLHSQGVVHRDLKPSNILYVDESG NPECLRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDEGCDIWSLGILLYTMLAGYTPFA NGPSDTPEEILTRIGSGKFTLSGGNWNTVSETAKDLVSKMLHVDPHQRLTAKQVLQHPWITQKDKLP QSQLSHQDLQLVKGAMAATYSALNSSKPTPQLKPIESSILAQRRVRKLPSTTL SEQ ID NO. 10: Mouse RSK2 >RSK2_mouse(P18654) MPLAQLADPWQKMAVESPSDSAENGQQIMDEPMGEEEINPQTEEGSIKEIAITHHVKEGHEKADPSQ FELLKVLGQGSFGKVFLVKKISGSDARQLYAMKVLKKATLKVRDRVRTKMERDILVEVNHPFIVKLH YAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALALDHLHSLGIIYRDLKPENILL DEEGHIKLTDFGLSKESIDHEKKAYSFCGTVEYMAPEVVNRRGHTQSADWWSFGVLMFEMLTGTLPF QGKDRKETMTMILKAKLGMPQFLSPEAQSLLRMLFKRNPANRLGAGPDGVEEIKRHSFFSTIDWNKL YRREIHPPFKPATGRPEDTFYFDPEFTAKTPKDSPGIPPSANAHQLFRGFSFVAITSDDESQAMQTV GVHSIVQQLHRNSIQFTDGYEVKEDIGVGSYSVCKRCIHKATNMEFAVKIIDKSKRDPTEEIEILLR YGQHPNIITLKDVYDDGKYVYVVTELMKGGELLDKILRQKFFSEREASAVLFTITKTVEYLHAQGVV HRDLKPSNILYVDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAACDIWS LGVLLYTMLTGYTPFANGPDDTPEEILARIGSGKFSLSGGYWNSVSDTAKDLVSKMLHVDPHQRLTA ALVLRHPWIVHWDQLPQYQLNRQDAPHLVKGAMAATYSALNRNQSPVLEPVGRSTLAQRRGIKKITS TAL SEQ ID NO. 11: Mouse RSK3 >RSK3_mouse(Q9WUT3) MELSMKKFTVRRFFSVYLRKKSRSKSSSLSRLEEEGIVKEIDISNHVKEGFEKADPSQFELLKVLGQ GSYGKVFLVRKVTGSDAGQLYAMKVLKKATLKVRDRVRSKMERDILAEVNHPFIVKLHYAFQTEGKL YLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALALDHLHGLGIIYRDLKPENILLDEEGHIKIT DFGLSKEATDHDKRAYSFCGTIEYMAPEVVNRRGHTQSADWWSFGVLMFEMLTGSLPFQGKDRKETM ALILKAKLGMPQFLSAEAQSLLRALFKRNPCNRLGAGVDGVEEIKRHPFFVTIDWNKLYRKEIKPPF KPAVGRPEDTFHFDPEFTARTPTDSPGVPPSANAHHLFRGFSFVASSLVQEPSQQDVPKAPIHPIVQ QLHGNNIHFTDGYEIKEDIGVGSYSVCKRCVHKATDAEYAVKIIDKSKRDPSEEIEILLRYGQHPNI ITLKDVYDDGKYVYLVMELMRGGELLDRILRQRCFSEREASDVLYTIARTMDYLHSQGVVHRDLKPS NILYMDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAACDVWSLGILLYT MLAGFTPFANGPDDTPEEILARIGSGKYALSGGNWDSISDAAKDVVSKMLHVDPQQRLTAVQVLKHP WIVNREYLSQNQLSRQDVHLVKGAMAATYFALNRTPQAPRLEPVLSSSLAQRRGMKRLTSTRL SEQ ID NO. 12: Mouse RSK4 >RSK4_mouse(Q7TPS0) MLPFAPVEDPWDQEDMEVFGSTSSSEPQVVFTMKNAATVMREHERKEVNDLKMVDEPMEEGEPVSCR REELVKEVPITQHVKEGYEKADPAQFDLLKVLGQGSFGKVFLVRKKTGPDAGQLYAMKVLRKASLKV RDRVRTKMERDILVEVNHPFIVKLHYAFQTEGKLYLILDFLRGGDVFTRLSKEVLFTEEDVKFYLAE LALALDHLHRLGIVYRDLKPENILLDEIGHIKLTDFGLSKESVDQEKKAYSFCGTVEYMAPEVVNRR AHSQSADWWSYGVLMFEMLTGTLPFQGKDRNETMNMILKAKLGMPQFLSAEAQSLLRMLFKRNPANR LGSEGVEEVKRHAFFASIDWNKLYKREVQPPFRPASGKPDDTFCFDPEFTAKTPKDSPGLPASANAH QLFKGFSFVATSIAEEYKITPVTSSNVLPIVQINGNAAQFSEAYELKEDIGIGSYSVCKRCIHSASN VEFAVKIIDKNKRDPSEEIEILMRYGQHPNIISLKEVFDDGKYVYLVTDLMKGGELLDRILKKKCFS EQEASNVLYVITKTVECLHSQGVVHRDLKPSNILYMDESAHPDSIKICDFGFAKQLRGENGLLLTPC YTANFVAPEVLTQQGYDAACDIWSLGVLLYTMLAGYTPFSNGPNDTPEEILLRIGNGRFSLSGGIWD NISRGAKDLLSHMLHMDPHQRYTAEQVLKHPWITQREQLPRHQPNSDEPPQEAVAAPYSVLARNPNR HHPILEPVTASRLAQRRNMKKRTSTGL SEQ ID NO. 13: Mouse MSK1 >MSK1_mouse(Q8C050) MEGEGGGSGGAGTSGDSGDGGEQLLTVKHELRTANLTGHAEKVGIENFELLKVLGTGAYGKVFLVRK ISGHDAGKLYAMKVLKKATIVQKAKTTEHTRTERQVLEHIRQSPFLVTLHYAFQTETKLHLILDYIN GGELFTHLSQRERFTEHEVQIYVGEIVLALEHLHKLGIIYRDIKLENILLDSNGHVVLTDFGLSKEF VADETERAYSFCGTIEYMAPDIVRGGDSGHDKAVDWWSLGVLMYELLTGASPFTVDGEKNSQAEISR RILKSEPPYPQEMSTVAKDLLQRLLMKDPKKRLGCGPRDAEEIKEHLFFEKIKWDDLAAKKVPAPFK PVIRDELDVSNFAEEFTEMDPTYSPAALPQSSERLFQGYSFVAPSILFKRNAAVIDPLQFHMGVDRP GVTNVARSAMMKDSPFYQHYDLDLKDKPLGEGSFSICRKCVHKKTNQAFAVKIISKRMEANTQKEIT ALKLCEGHPNIVKLHEVFHDQVAASAQPPGQVVLCSLLLLALLFNRSLTRKPVTVVTWLVHSTSQLP PLPPPMPEIVLFILLSDNGQLHTFLVMELLNGGELFERIKRKKHFSETEASYIMRKLVSAVSHMHDV GVVHRDLKPENLLFTDENDNLEIKVIDFGFARLKPPDNQPLKTPCFTLHYAAPELLTHNGYDESCDL WSLGVILYTMLSGQVPFQSHDRSLTCTSAVEIMKKIKKGDFSFEGEAWKNVSQEAKDLIQGLLTVDP NKRLKMSGLRYNEWLQDGSQLSSNPLMTPDILGSSGAAVHTCVKATFHAFNKYKREGFCLQNVDKAP LAKRRKMKRTSTSTETRSSSSESSRSSSSQSHGKTTPTKTLQPSNPTEGSNPDTLFQFSD SEQ ID NO. 14: Mouse MSK2 >MSK2_mouse(Q9Z2B9) MGDEDEDEGCAVELQITEANLTGHEEKVSVENFALLKVLGTGAYGKVFLVRKTGGHDAGKLYAMKVL RKAALVQRAKTQEHTRTERSVLELVRQAPFLVTLHYAFQTDAKLHLILDYVSGGEMFTHLYQRQYFK EAEVRVYGGEIVLALEHLHKLGIIYRDLKLENVLLDSEGHIVLTDFGLSKEFLTEEKERTFSFCGTI EYMAPEIIRSKAGHGKAVDWWSLGILLFELLTGASPFTLEGERNTQAEVSRRILKCSPPFPLRIGPV AQDLLQRLLCKDPKKRLGAGPQGAQEVKSHPFFQGLDWVALAARKIPAPFRPQIRSELDVGNFAEEF TRLEPVYSPAGSPPPGDPRIFQGYSFVAPSILFDHNNAVMADVLQAPGAGYRPGRAAVARSAMMQDS PFFQQYELDLREPALGQGSFSVCRRCRQRQSGQEFAVKILSRRLEENTQREVAALRLCQSHPNVVNL HEVLHDQLHTYLVLELLRGGELLEHIRKKRLFSESEASQILRSLVSAVSFMHEEAGVVHRDLKPENI LYADDTPGAPVKIIDFGFARLRPQSPAEPMQTPCFTLQYAAPELLAQQGYDESCDLWSLGVILYMML SGQVPFQGASGQGGQSQAAEIMCKIREGRFSLDGEAWQGVSEEAKELVRGLLTVDPAKRLKLEGLRS SSWLQDGSARSSPPLRTPDVLESSGPAVRSGLNATFMAFNRGKREGFFLKSVENAPLAKRRKQKLRS AAASRRGSPVPASSGRLPASAAKGTTRRANGPLSPS SEQ ID NO. 15: Rat RSK1 >RSK1_rat(Q63531) MPLAQLKEPWPLMELVPLDPENGQASGEEAGLQPSKDEGILKEISITHHVKAGSEKADPSHFELLKV LGQGSFGKVFLVRKVTRPDNGHLYAMKVLKKATLKVRDRVRTKMERDILADVNHPFVVKLHYAFQTE GKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALGLDHLHSLGIIYRDLKPENILLDEEGHI KLTDFGLSKEAIDHEKKAYSFCGTVEYMAPEVVNRQGHTHSADWWSYGVLMFEMLTGSLPFQGKDRK ETMTLILKAKLGMPQFLSTEAQSLLRALFKRNPANRLGSGPDGAEEIKRHIFYSTIDWNKLYRREIK PPFKPAVAQPDDTFYFDTEFTSRTPRDSPGIPPSAGAHQLFRGFSFVATGLMEDDSKPRATQAPLHS VVQQLHGKNLVFSDGYIVKETIGVGSYSVCKRCVHKATNMEYAVKVIDKSKRDPSEEIEILLRYGQH PNIITLKDVYDDSKHVYLVTELMRGGELLDKILRQKFFSEREASFVLYTISKTVEYLHSQGVVHRDL KPSNILYVDESGNPECLRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDEGCDIWSLGVL LYTMLAGYTPFANGPSDTPEEILTRISSGKFTLSGGNWNTVSETAKDLVSKMLHVDPHQRLTAKQVL QHPWITQKDKLPQSQLSHQDLQLVKGGMAATYSALSSSKPTPQLKPIESSILAQRRVRKLPSTTL SEQ ID NO. 16: Rat RSK2 >RSK2_rat(NP_001178933.1) MPLAQLADPWQKMAVESPSDSAENGQQIMDEPMGEEEINPQTEEGSIKEIAITHHVKEGHEKADPSQ FELLKVLGQGSFGKVFLVKKISGSDARQLYAMKVLKKATLKVRDRVRTKMERDILVEVNHPFIVKLH YAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALALDHLHSLGIIYRDLKPENILL DEEGHIKLTDFGLSKESIDHEKKAYSFCGTVEYMAPEVVNRRGHTQSADWWSFGVLMFEMLTGTLPF QGKDRKETMTMILKAKLGMPQFLSPEAQSLLRMLFKRNPANRLGAGPDGVEEIKRHSFFSTIDWNKL YRREIHPPFKPATGRPEDTFYFDPEFTAKTPKDSPGIPPSANAHQLFRGFSFVAITSDDESQAMQTV GVHSIVQQLHRNSIQFTDGYEVKEDIGVGSYSVCKRCIHKATNMEFAVKIIDKSKRDPTEEIEILLR YGQHPNIITLKDVYDDGKYVYVVTELMKGGELLDKILRQKFFSEREASAVLFTITKTVEYLHTQGVV HRDLKPSNILYVDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAACDIWS LGVLLYTMLTGYTPFANGPDDTPEEILARIGSGKFSLSGGYWNSVSDTAKDLVSKMLHVDPHQRLTA ALVLRHPWIVHWDQLPQYQLNRQDAPHLVKGAMAATYSALNRNQSPVLEPVGRSTLAQRRGIKKITS TAL SEQ ID NO. 17: Rat RSK3 >RSK3_rat(NP_476469.1) MELNMKKFTVRRFFSVYLRKKSRSKSSSLSRLEEEGIVKEIDISSHVKEGFEKADPSQFELLKVLGQ GSYGKVFLVRKVTGSDAGQLYAMKVLKKATLKVRDRVRSKMERDILAEVNHPFIVKLHYAFQTEGKL YLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALALDHLHGLGIIYRDLKPENILLDEEGHIKIT DFGLSKEAIDHDKRAYSFCGTIEYMAPEVVNRRGHTQSADWWSFGVLMFEMLTGSLPFQGKDRKETM ALILKAKLGMPQFLSAEAQSLLRALFKRNPCNRLGAGVDGVEEIKRHPFFVTIDWNKLYRKEIKPPF KPAVGRPEDTFHFDPEFTARTPTDSPGVPPSANAHHLFRGFSFVASSLVQEPSQQDVPKAPIHPIVQ QLHGNNIHFTDGYEIKEDIGVGSYSVCKRCVHKATDAEYAVKIIDKSKRDPSEEIEILLRYGQHPNI ITLKDVYDDGKYVYLVMELMRGGELLDRILRQRCFSEREASDVLYTIARTMDYLHSQGVVHRDLKPS NILYMDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAACDVWSLGILLYT MLAGFTPFANGPDDTPEEILARIGSGKYALSGGNWDSISDAAKDVVSKMLHVDPQQRLTAVQVLKHP WIVNREYLSQNQLSRQDVHLVKGAMAATYFALNRTPQAPRLEPVLSSSLAQRRGMKRLTSTRL SEQ ID NO. 18: Rat RSK4 >RSK4_rat(NP_001178650.1) MLNFRRTRHTPSGHRSNSSLNLFCCFPFFGCRRQSRSRQRAGTPVVPLLRYPPLARSAVTQRESWSY EEDHEPAQQAGCMLVLGTSSFFSSVPEAAMLPFAPVEDPWDEEMEVFGSGSTSSSEPQIVFTMKTAA MVIRQHEHKEVNDLKMVDEPMDEGEPVFCRREDLVKEIPITQHVKEGYEKADPAQFDLLKVLGQGSF GKVFLVRKKTGPDAGQLYAMKVLRKASLKVRDRVRTKMERDILVEVNHPFIVKLHYAFQTEGKLYLI LDFLRGGDVFTRLSKEVLFTEEDVKFYLAELALALDHLHRLGIVYRDLKPENILLDEIGHIKLTDFG LSKESVDQEKKAYSFCGTVEYMAPEVVNRRGHSQSADWWSYGVLMFEMLTGTLPFQGKDRNETMNMI LKAKLGMPQFLSAEAQSLLRMLFKRNPANRLGSEGVEEVKRHAFFSSIDWNKLYKREVQPPFRPASG KPDDTFCFDPEFTAKTPKDSPGLPASANAHQLFKGFSFVATSIAEEYKITPVTSSNVLPIVQINGNA AQFSEAYELKEDIGIGSYSVCKRCIHSASNMEFAVKIIDKNKRDPSEEIEILMRYGQHPNIISLKEV FDDGKYVYLVTDLMKGGELLDRILKKKCFSEQEASNVLYVITKTVEYLHSQGVVHRDLKPSNILYMD ESGHPDSIKICDFGFAKQLRGENGLLLTPCYTANFVAPEVLTQQGYDAACDIWSLGVLLYTMLAGYT PFSNGPNDTPEEILLRIGNGRFSLSGGIWDNISRGAKDLLSHMLHMDPHQRYTAEQVLKHPWITQRE QLPRHQPTSDDPPQEAVAAAYSVLARNQNRHPILEPVAASRLAQRRNMKKRTSTGL SEQ ID NO. 19: Rat MSK1 >MSK1_rat(NP_001101518.1) MEGEGGGSGGAGTSGDSGDGGEQLLTVKHELRTANLTGHAEKVGIENFELLKVLGTGAYGKVFLVRK ISGHDAGKLYAMKVLKKATIVQKAKTTEHTRTERQVLEHIRQSPFLVTLHYAFQTETKLHLILDYIN GGELFTHLSQRERFTEHEVQIYVGEIVLALEHLHKLGIIYRDIKLENILLDSNGHVVLTDFGLSKEF VADEAERAYSFCGTIEYMAPDIVRGGDSGHDKGMSSVAKDLLQRLLMKDPKKRLGCGPRDAEEIKEH LFFEKINWDDLAAKKVPAPFKPVIRDELDVSNFAEEFTEMDPTYSPAALPQSSERLFQGYSFVAPSI LFKRNAAVIDPLQFHMGVDRPGVTNVARSAMMKDSPFYQHYDLDLKDKPLGEGSFSICRKCVHKKTN QAFAVKIISKRMEANTQKEITALKLCEGHPNVVKLHEVFHDQLHTFLVMELLNGGELFERIKKKKHF SETEASYIMRKLVSAVSHMHDVGVVHRDLKPETVFHREISRSPVISMRIPEYTLQNLLFTDENDNLE IKVIDFGFARLKPPDNQPLKTPCFTLHYAAPELLTHNGYDESCDLWSLGVILYTMLSGQVPFQSHDR SLTCTSAVEIMKKIKKGDFSFEGEAWKNVSQEAKDLIQGLLTVDPNKRLKMSGLRYNEWLQDGSQLS SNPLMTPDILGSSGAAVHTCVKATFHAFNKYKREGFCLQNVDKAPLAKRRKMKRTSTSTETRSSSSE SSRSSSSHSHGKTTPTKTLQPSNPTEGSNPDTLFQFSD SEQ ID NO. 20: Rat MSK2 >MSK2_rat(NP_001101987.2) MGDEDEDEGCAVELQITEANLTGHEEKVSVENFALLKVLGTGAYGKVFLVRKAGGHDAGKLYAMKVL RKAALVQRAKTQEHTRTERSVLELVRQAPFLVTLHYAFQTDAKLHLILDYVSGGEMFTHLYQRQYFK EAEVRVYGGEIVLALEHLHKLGIIYRDLKLENVLLDSEGHIVLTDFGLSKEFLTEEKERTFSFCGTI EYMAPEIIRSKAGHGKAVDWWSLGILLFELLTGASPFTLEGERNTQAEVSRRILKCSPPFPPRIGPV AQDLLQRLLCKDPKKRLGAGPQGAQEVKSHLFFQGLDWVALAARKIPAPFRPQIRSELDVGNFAEEF TRLEPVYSPAGSPPPGDPRIFQGYSFVAPSILFDHNNAVMADVLAAPGAGYRPGRAAVARSAMMQDS PFFQQYELDLREPALGQGSFSVCRRCRQRQSGQEFAVKILSRRLEENTQREVAALRLCQSHPNVVNL HEVLHDQLHTYLVLELLRGGELLEHIRKKRLFSESEASQILRSLVSAVSFMHEEAGVVHRDLKPENI LYADDTPGAPVKIIDFGFARLRPQSPAGPMQTPCFTLQYAAPELLAQQGYDESCDLWSLGVILYMML SGQVPFQGASGQGGQSQAAEIMCKIREGRFSLDGEAWQGVSEEAKELVRGLLTVDPAKRLKLEGLRS SSWLQDGSARSSPPLRTPDVLESSGPAVRSGLNATFMAFNRGKREGFFLKSVENAPLAKRRKQKLRS AAASRRGSPVPASSGRLPASASKGTTRRANGPLSPS

Example 2 Ribosomal S6 Kinase 2 Expression and Purification

A construct of the C-terminal kinase domain of murine Ribosomal S6 Kinase 2 (RSK2) (residues 400-740; SEQ ID NO. 2) including a N-terminal polyhistidine tag (His₈), a linker (DYDIPTT) (SEQ ID NO: 21) and a Tobacco Etch Virus (TEV) protease site (ENLYFQG) (SEQ ID NO: 22) in the expressed kinase was designed and ordered from Genscript. The synthesised gene was subcloned into pET-22b (Novagen) by the vendor resulting in RSK2-pET-22b. B121 (DE3) Rosetta was transformed with RSK2-pET-22b and plated on lysogeny broth (LB) agar plates supplemented with 50 μg/ml ampicillin (Amp) and 35 μg/ml Chloramphenicol (Cam). 5 colonies were used for inoculation of a 20 ml LB overnight culture supplemented with 100 μg/ml Amp and 35 μg/ml Cam. 2 litres of LB, supplemented with 100 μg/ml Amp and 35 μg/ml Cam, was inoculated with the overnight culture and grown at 37° C. Expression was induced with 0.1 mM isopropyl β-D-1-thiogalactopyranoside at an optical density of A_(600 nm)=0.8 and the temperature was lowered to 20° C. for 3 h and further lowered to 12° C. for 20 hours. 8 g cells were harvested from 2 l of culture and resuspended in 100 ml of lysis-buffer (50 mM Tris-HCl, 100 mM NaCl and 5 mM β-mercaptoethanol, pH 7.5). Cells were lysed by high-pressure homogenisation (three times at 15.000 psi) in lysis-buffer supplemented with 1 mM PMSF and 5 μg/ml DNase I. The lysate was cleared of cell debris and aggregates by centrifugation at 25.000 g for 45 minutes. 5 ml of Ni²⁺-beads slurry (Ni-sepharose 6 Fast Flow, GE Healthcare) were washed in equilibration-buffer (20 mM Tris-HCl, 100 mM NaCl, 5 mM β-mercaptoethanol, pH 7.5) and incubated with supernatant for 1 h at room temperature. The supernatant and Ni²⁺-beads were poured into a Poly-Prep column (Bio-Rad) and washed with 100 ml equilibration-buffer. RSK2 was eluted in two times 5 ml elution-buffer (20 mM TrisHCl, 100 mM NaCl, 5 mM β-mercaptoethanol, 500 mM imidazole, pH 7.5). The eluate was supplemented with 1 mg of recombinant TEV and immediately dialysed against 1 l of equilibration-buffer overnight at room temperature. Digested and dialysed RSK2 was loaded on the Ni-beads in the Poly-Prep column and RSK2 was collected in the flow through. RSK2 was concentrated by ultrafiltration (Vivaspin 6, 30 kDa cutoff). Protein concentration was evaluated by spectrophotometry (Nanodrop, Thermo Fisher Scientific) assuming ε_(RSK2)=44350 cm⁻¹ M⁻¹ and M_(RSK2)=38.4 kDa. Size exclusion chromatography (SEC) was performed on a Superdex 200 10/300 GL (GE Healthcare) column in SEC-buffer (10 mM TrisHCl, 50 mM NaCl, 5 mM β-mercaptoethanol, pH 8.0) at room temperature. Fractions containing RSK2 were concentrated by ultrafiltration to 10 mg/ml (Vivaspin 6, 30 kDa cut off) and during concentration the buffer was exchanged to 10 mM TrisHCl pH 8.0, 10 mM β-mercaptoethanol. RSK2 was aliquoted, flash frozen in liquid N₂ and stored at −80° C. RSK2 purity was evaluated by SDS-PAGE using a 15% separation gel. RSK2 was dialysed into reactions buffer (10 mM TrisHCl pH 8.0 and 5 mM Tris(2-carboxyethyl)phosphine (TCEP)) in a slide-A-lyzer (Thermo Fisher) prior to reaction with dimethyl fumarate for ligand assays and crystallisation. The purification procedure resulted >95% pure and stable RSK2 evaluated by SDS-PAGE and mass spectrometry.

Example 3 Crystallisation

The RSK2-DMF complex was formed by mixing RSK2 (SEQ ID NO: 1) (8 mg/ml) dialysed into reaction buffer with 5 mM DMF and incubating 30 min at room temperature. Aggregated RSK2 was removed by centrifugation at 15.000 g for 5 min. Initial screening was performed using Index screen (Hampton Research) where 1 μl RSK2 was mixed with 1 μl reservoir solution and equilibrated against 500 μl reservoir using the sitting-drop vapour-diffusion method at 19° C. An initial crystal hit was obtained in condition #43 (0.1 M Bis-Tris pH 6.5 and 25% (w/v) polyethylene glycol (PEG) 3350). The size and diffraction properties of the crystals were optimized with Additive Screen HT (Hampton Research) with condition #19 (0.05 M NaF). Crystals were reproducibly obtained in the described condition in a size suitable for data collection.

Example 4 Data Collection, Processing and Refinement

Crystals were mounted in nylon loops from mother liquor supplemented with 20% (v/v) Ethylene glycol and flash cooled in liquid N₂. A complete data-set was collected at 100 K on the X06SA beamline at the Swiss Light Source (Paul Scherrer Institute). The diffraction images were processed using XDS⁵³. Molecular replacement was performed with the program PHASER⁵⁴ and a search model derived from PDB ID 2QR8⁴⁷. Rigid body refinement, refinement and calculation of omit maps were performed in the PHENIX suite⁵⁵. Model building and analysis was performed with Coot⁵⁶. A complete data set scaling to 1.9 Å resolution with good statistics was collected. Phases were obtained by molecular replacement and the structure of RSK2 with DMF bound was refined to acceptable geometry and R-factors.

TABLE 1 Data statistics Beamline X06SA (SLS) Wavelength (Å) 0.9 Resolution range 47.0-1.9 Space group P4₁2₁2 Unit cell parameters (Å) a = b = 47.0 and c = 291.9 Mosaicity (°) 0.1 Unique reflections 27094 Multiplicity 8.6 Mean l/σ(l) 23.3 (2.3) Completeness (%) 99.4 (96.5) R_(meas) (%) 3.7 (88.8) R_(p.i.m) 1.3 (32.1) Molecules per asymmetric unit 1 Solvent content (%) 48.7 Matthews coefficient (Å³ Da⁻¹) 2.39

TABLE 2 Refinement statistics R/R_(free) (%) 19.5/24.6 Bond length (Å)/bond angle (°) 0.007/1.043 Overall B factor from Wilson plot (Å²) 42.2 B-factors (Å²) Protein 64.1 Dimethyl fumarate 61.8 Waters 58.8 Ramachandran plot (%) Most favored region 96.0 Allowed region 3.3 Outlier region 0.7

TABLE 3 Atomic coordinates of RSK2 model (pdb file) ATOM 1 O VAL A 408 −29.990 9.813 6.893 1.00 129.22 O ATOM 2 N VAL A 408 −27.851 11.711 6.085 1.00 124.97 N ATOM 3 CA VAL A 408 −28.040 10.345 5.612 1.00 126.54 C ATOM 4 C VAL A 408 −29.506 9.936 5.765 1.00 131.99 C ATOM 5 CB VAL A 408 −27.165 9.353 6.413 1.00 118.17 C ATOM 6 CG1 VAL A 408 −25.860 10.007 6.844 1.00 106.36 C ATOM 7 CG2 VAL A 408 −26.904 8.090 5.601 1.00 118.04 C ATOM 8 O GLN A 409 −31.963 10.617 2.848 1.00 136.09 O ATOM 9 N GLN A 409 −30.224 9.729 4.657 1.00 135.16 N ATOM 10 CA GLN A 409 −29.717 9.877 3.291 1.00 133.31 C ATOM 11 C GLN A 409 −30.875 10.288 2.374 1.00 136.40 C ATOM 12 CB GLN A 409 −29.127 8.549 2.803 1.00 129.08 C ATOM 13 CG GLN A 409 −27.798 8.673 2.079 1.00 125.42 C ATOM 14 CD GLN A 409 −27.959 9.036 0.621 1.00 124.14 C ATOM 15 OE1 GLN A 409 −28.921 8.625 −0.030 1.00 125.64 O ATOM 16 NE2 GLN A 409 −27.023 9.817 0.099 1.00 120.76 N ATOM 17 O GLN A 410 −33.283 8.719 −0.475 1.00 144.07 O ATOM 18 N GLN A 410 −30.647 10.271 1.065 1.00 140.18 N ATOM 19 CA GLN A 410 −31.736 10.454 0.112 1.00 139.98 C ATOM 20 C GLN A 410 −32.115 9.110 −0.497 1.00 139.47 C ATOM 21 CB GLN A 410 −31.361 11.454 −0.986 1.00 142.41 C ATOM 22 CG GLN A 410 −32.392 12.571 −1.204 1.00 144.67 C ATOM 23 CD GLN A 410 −33.708 12.085 −1.811 1.00 144.58 C ATOM 24 OE1 GLN A 410 −33.788 10.985 −2.363 1.00 148.55 O ATOM 25 NE2 GLN A 410 −34.746 12.911 −1.711 1.00 138.39 N ATOM 26 O LEU A 411 −31.217 5.801 0.419 1.00 116.84 O ATOM 27 N LEU A 411 −31.124 8.402 −1.032 1.00 133.05 N ATOM 28 CA LEU A 411 −31.361 7.085 −1.615 1.00 129.09 C ATOM 29 C LEU A 411 −31.887 6.096 −0.575 1.00 128.15 C ATOM 30 CB LEU A 411 −30.094 6.536 −2.278 1.00 125.31 C ATOM 31 CG LEU A 411 −29.563 7.270 −3.512 1.00 119.72 C ATOM 32 CD2 LEU A 411 −30.698 7.854 −4.339 1.00 113.47 C ATOM 33 CD1 LEU A 411 −28.699 6.335 −4.353 1.00 116.24 C ATOM 34 O HIS A 412 −33.887 2.696 −1.271 1.00 132.76 O ATOM 35 N HIS A 412 −33.097 5.598 −0.816 1.00 133.67 N ATOM 36 CA HIS A 412 −33.767 4.673 0.092 1.00 136.06 C ATOM 37 C HIS A 412 −34.500 3.602 −0.703 1.00 135.41 C ATOM 38 CB HIS A 412 −34.786 5.423 0.954 1.00 136.48 C ATOM 39 CG HIS A 412 −34.177 6.427 1.880 1.00 137.17 C ATOM 40 ND1 HIS A 412 −32.946 6.243 2.473 1.00 137.23 N ATOM 41 CD2 HIS A 412 −34.631 7.625 2.319 1.00 137.64 C ATOM 42 CE1 HIS A 412 −32.669 7.283 3.237 1.00 138.79 C ATOM 43 NE2 HIS A 412 −33.674 8.137 3.160 1.00 139.12 N ATOM 44 O ARG A 413 −38.732 3.025 −0.154 1.00 137.84 O ATOM 45 N ARG A 413 −35.825 3.737 −0.716 1.00 136.48 N ATOM 46 CA ARG A 413 −36.740 2.908 −1.495 1.00 135.59 C ATOM 47 C ARG A 413 −38.167 3.369 −1.193 1.00 137.33 C ATOM 48 CB ARG A 413 −36.578 1.425 −1.155 1.00 133.58 C ATOM 49 CG ARG A 413 −37.300 0.490 −2.108 1.00 131.73 C ATOM 50 CD ARG A 413 −36.824 −0.947 −1.941 1.00 132.45 C ATOM 51 NE ARG A 413 −37.033 −1.451 −0.584 1.00 134.15 N ATOM 52 CZ ARG A 413 −38.081 −2.177 −0.204 1.00 132.79 C ATOM 53 NH1 ARG A 413 −39.029 −2.495 −1.077 1.00 132.54 N ATOM 54 NH2 ARG A 413 −38.179 −2.590 1.053 1.00 129.67 N ATOM 55 O ASN A 414 −41.028 2.572 −2.299 1.00 126.87 O ATOM 56 N ASN A 414 −38.737 4.159 −2.098 1.00 136.05 N ATOM 57 CA ASN A 414 −40.064 4.746 −1.901 1.00 132.80 C ATOM 58 C ASN A 414 −41.224 3.755 −2.015 1.00 126.57 C ATOM 59 CB ASN A 414 −40.284 5.902 −2.889 1.00 134.06 C ATOM 60 CG ASN A 414 −39.865 7.246 −2.324 1.00 135.51 C ATOM 61 OD1 ASN A 414 −40.271 7.622 −1.224 1.00 136.08 O ATOM 62 ND2 ASN A 414 −39.050 7.980 −3.077 1.00 132.85 N ATOM 63 O SER A 415 −44.266 2.791 −4.246 1.00 110.34 O ATOM 64 N SER A 415 −42.432 4.257 −1.776 1.00 118.82 N ATOM 65 CA SER A 415 −43.660 3.507 −2.025 1.00 111.36 C ATOM 66 C SER A 415 −44.043 3.727 −3.481 1.00 111.15 C ATOM 67 CB SER A 415 −44.784 4.043 −1.137 1.00 106.30 C ATOM 68 OG SER A 415 −45.997 3.346 −1.362 1.00 104.38 O ATOM 69 O ILE A 416 −42.161 5.349 −6.030 1.00 78.90 O ATOM 70 N ILE A 416 −44.109 5.004 −3.831 1.00 104.49 N ATOM 71 CA ILE A 416 −44.409 5.467 −5.169 1.00 93.98 C ATOM 72 C ILE A 416 −43.340 5.019 −6.165 1.00 69.29 C ATOM 73 CB ILE A 416 −44.510 6.984 −5.169 1.00 101.27 C ATOM 74 CG1 ILE A 416 −43.408 7.568 −4.282 1.00 108.71 C ATOM 75 CG2 ILE A 416 −45.870 7.416 −4.643 1.00 98.29 C ATOM 76 CD1 ILE A 416 −43.294 9.084 −4.296 1.00 110.46 C ATOM 77 N GLN A 417 −43.757 4.256 −7.167 1.00 94.62 N ATOM 78 CA GLN A 417 −42.838 3.785 −8.197 1.00 77.33 C ATOM 79 C GLN A 417 −42.767 4.760 −9.373 1.00 80.01 C ATOM 80 O GLN A 417 −43.716 5.505 −9.653 1.00 64.65 O ATOM 81 CB GLN A 417 −43.252 2.394 −8.680 1.00 83.50 C ATOM 82 CG GLN A 417 −43.323 1.354 −7.579 1.00 87.24 C ATOM 83 CD GLN A 417 −42.318 0.232 −7.767 1.00 97.42 C ATOM 84 OE1 GLN A 417 −41.173 0.466 −8.150 1.00 98.83 O ATOM 85 NE2 GLN A 417 −42.752 −1.000 −7.515 1.00 105.59 N ATOM 86 N PHE A 418 −41.631 4.750 −10.057 1.00 71.46 N ATOM 87 CA PHE A 418 −41.440 5.607 −11.210 1.00 69.51 C ATOM 88 C PHE A 418 −42.492 5.309 −12.269 1.00 67.13 C ATOM 89 O PHE A 418 −42.974 6.213 −12.945 1.00 66.63 O ATOM 90 CB PHE A 418 −40.039 5.413 −11.784 1.00 72.46 C ATOM 91 CG PHE A 418 −39.821 6.113 −13.089 1.00 69.66 C ATOM 92 CD1 PHE A 418 −39.833 7.498 −13.158 1.00 65.59 C ATOM 93 CD2 PHE A 418 −39.595 5.388 −14.246 1.00 64.89 C ATOM 94 CE1 PHE A 418 −39.625 8.150 −14.365 1.00 63.62 C ATOM 95 CE2 PHE A 418 −39.385 6.031 −15.449 1.00 74.14 C ATOM 96 CZ PHE A 418 −39.403 7.416 −15.511 1.00 71.95 C ATOM 97 N THR A 419 −42.859 4.036 −12.380 1.00 74.14 N ATOM 98 CA THR A 419 −43.819 3.560 −13.375 1.00 80.84 C ATOM 99 C THR A 419 −45.224 4.103 −13.127 1.00 81.68 C ATOM 100 O THR A 419 −46.078 4.083 −14.016 1.00 93.16 O ATOM 101 CB THR A 419 −43.896 2.015 −13.366 1.00 92.79 C ATOM 102 OG1 THR A 419 −42.582 1.465 −13.222 1.00 101.76 O ATOM 103 CG2 THR A 419 −44.523 1.493 −14.647 1.00 94.97 C ATOM 104 N ASP A 420 −45.460 4.586 −11.915 1.00 73.49 N ATOM 105 CA ASP A 420 −46.790 5.027 −11.519 1.00 82.79 C ATOM 106 C ASP A 420 −47.118 6.433 −11.996 1.00 82.88 C ATOM 107 O ASP A 420 −48.253 6.713 −12.382 1.00 86.87 O ATOM 108 CB ASP A 420 −46.938 4.945 −10.004 1.00 84.17 C ATOM 109 CG ASP A 420 −46.853 3.529 −9.496 0.35 81.78 C ATOM 110 OD1 ASP A 420 −47.368 2.621 −10.180 1.00 82.62 O ATOM 111 OD2 ASP A 420 −46.261 3.323 −8.421 1.00 76.57 O ATOM 112 N GLY A 421 −46.123 7.314 −11.965 1.00 71.47 N ATOM 113 CA GLY A 421 −46.316 8.689 −12.390 1.00 72.52 C ATOM 114 C GLY A 421 −45.795 8.994 −13.783 1.00 67.40 C ATOM 115 O GLY A 421 −46.120 10.037 −14.365 1.00 67.06 O ATOM 116 N TYR A 422 −44.990 8.086 −14.331 1.00 57.07 N ATOM 117 CA TYR A 422 −44.384 8.318 −15.641 1.00 60.05 C ATOM 118 C TYR A 422 −44.606 7.177 −16.620 1.00 64.60 C ATOM 119 O TYR A 422 −44.629 6.008 −16.233 1.00 59.66 O ATOM 120 CB TYR A 422 −42.882 8.583 −15.488 1.00 55.61 C ATOM 121 CG TYR A 422 −42.566 9.836 −14.705 1.00 52.03 C ATOM 122 CD1 TYR A 422 −42.328 11.046 −15.352 1.00 57.30 C ATOM 123 CD2 TYR A 422 −42.512 9.814 −13.317 1.00 57.96 C ATOM 124 CE1 TYR A 422 −42.038 12.197 −14.631 1.00 41.10 C ATOM 125 CE2 TYR A 422 −42.229 10.952 −12.594 1.00 53.76 C ATOM 126 CZ TYR A 422 −41.997 12.139 −13.252 1.00 46.21 C ATOM 127 OH TYR A 422 −41.715 13.266 −12.529 1.00 48.13 O ATOM 128 N GLU A 423 −44.779 7.533 −17.889 1.00 64.97 N ATOM 129 CA GLU A 423 −44.781 6.566 −18.979 1.00 71.15 C ATOM 130 C GLU A 423 −43.432 6.629 −19.677 1.00 74.66 C ATOM 131 O GLU A 423 −43.031 7.675 −20.183 1.00 73.44 O ATOM 132 CB GLU A 423 −45.898 6.858 −19.992 1.00 76.67 C ATOM 133 CG GLU A 423 −47.302 6.769 −19.422 1.00 90.10 C ATOM 134 CD GLU A 423 −48.347 7.360 −20.346 1.00 95.73 C ATOM 135 OE1 GLU A 423 −49.516 7.483 −19.917 1.00 103.18 O ATOM 136 OE2 GLU A 423 −47.997 7.702 −21.498 1.00 91.66 O ATOM 137 N VAL A 424 −42.732 5.505 −19.698 1.00 70.20 N ATOM 138 CA VAL A 424 −41.428 5.427 −20.337 1.00 67.69 C ATOM 139 C VAL A 424 −41.562 5.327 −21.853 1.00 72.98 C ATOM 140 O VAL A 424 −42.348 4.534 −22.375 1.00 77.26 O ATOM 141 CB VAL A 424 −40.628 4.221 −19.793 1.00 70.59 C ATOM 142 CG1 VAL A 424 −39.482 3.850 −20.721 1.00 68.34 C ATOM 143 CG2 VAL A 424 −40.117 4.525 −18.394 1.00 66.58 C ATOM 144 N LYS A 425 −40.790 6.136 −22.562 1.00 68.02 N ATOM 145 CA LYS A 425 −40.808 6.079 −24.010 1.00 73.63 C ATOM 146 C LYS A 425 −39.445 5.707 −24.583 1.00 76.36 C ATOM 147 O LYS A 425 −38.695 4.927 −23.989 1.00 81.23 O ATOM 148 CB LYS A 425 −41.321 7.400 −24.592 1.00 73.69 C ATOM 149 CG LYS A 425 −42.784 7.667 −24.274 1.00 77.85 C ATOM 150 CD LYS A 425 −43.652 6.484 −24.691 1.00 84.09 C ATOM 151 CE LYS A 425 −45.126 6.725 −24.412 1.00 83.50 C ATOM 152 NZ LYS A 425 −45.947 5.519 −24.725 1.00 88.52 N ATOM 153 N GLU A 426 −39.142 6.283 −25.739 1.00 75.33 N ATOM 154 CA GLU A 426 −37.965 5.950 −26.535 1.00 76.64 C ATOM 155 C GLU A 426 −36.659 6.233 −25.809 1.00 77.88 C ATOM 156 O GLU A 426 −36.622 7.022 −24.869 1.00 70.53 O ATOM 157 CB GLU A 426 −38.011 6.762 −27.831 1.00 68.53 C ATOM 158 CG GLU A 426 −39.126 7.816 −27.818 1.00 58.09 C ATOM 159 CD GLU A 426 −38.631 9.204 −28.151 1.00 73.18 C ATOM 160 OE1 GLU A 426 −37.398 9.400 −28.213 1.00 87.31 O ATOM 161 OE2 GLU A 426 −39.478 10.100 −28.352 1.00 78.58 O ATOM 162 N ASP A 427 −35.584 5.592 −26.263 1.00 84.75 N ATOM 163 CA ASP A 427 −34.242 5.907 −25.782 1.00 81.34 C ATOM 164 C ASP A 427 −33.802 7.262 −26.314 1.00 69.87 C ATOM 165 O ASP A 427 −34.156 7.643 −27.429 1.00 79.90 O ATOM 166 CB ASP A 427 −33.236 4.850 −26.249 1.00 90.94 C ATOM 167 CG ASP A 427 −33.479 3.492 −25.627 1.00 99.76 C ATOM 168 OD1 ASP A 427 −32.890 3.214 −24.562 1.00 96.02 O ATOM 169 OD2 ASP A 427 −34.249 2.699 −26.208 1.00 107.76 O ATOM 170 N ILE A 428 −33.027 7.991 −25.519 1.00 67.31 N ATOM 171 CA ILE A 428 −32.446 9.247 −25.984 1.00 75.99 C ATOM 172 C ILE A 428 −30.930 9.156 −25.992 1.00 75.26 C ATOM 173 O ILE A 428 −30.260 9.859 −26.745 1.00 87.11 O ATOM 174 CB ILE A 428 −32.814 10.441 −25.084 1.00 79.16 C ATOM 175 CG1 ILE A 428 −34.257 10.356 −24.600 1.00 85.42 C ATOM 176 CG2 ILE A 428 −32.567 11.759 −25.813 1.00 75.68 C ATOM 177 CD1 ILE A 428 −34.579 11.425 −23.579 1.00 79.00 C ATOM 178 N GLY A 429 −30.385 8.303 −25.133 1.00 79.96 N ATOM 179 CA GLY A 429 −28.946 8.182 −25.031 1.00 89.62 C ATOM 180 C GLY A 429 −28.474 6.935 −24.318 1.00 101.29 C ATOM 181 O GLY A 429 −29.235 5.993 −24.089 1.00 102.80 O ATOM 182 N VAL A 430 −27.197 6.943 −23.957 1.00 106.38 N ATOM 183 CA VAL A 430 −26.553 5.787 −23.365 1.00 106.87 C ATOM 184 C VAL A 430 −25.480 6.265 −22.395 1.00 116.42 C ATOM 185 O VAL A 430 −25.110 7.440 −22.391 1.00 122.79 O ATOM 186 CB VAL A 430 −25.895 4.921 −24.457 1.00 99.37 C ATOM 187 CG1 VAL A 430 −24.593 5.561 −24.928 1.00 103.44 C ATOM 188 CG2 VAL A 430 −25.661 3.496 −23.966 1.00 93.65 C ATOM 189 N GLY A 431 −24.997 5.354 −21.562 1.00 116.25 N ATOM 190 CA GLY A 431 −23.838 5.614 −20.738 1.00 115.28 C ATOM 191 C GLY A 431 −22.939 4.395 −20.710 1.00 116.92 C ATOM 192 O GLY A 431 −21.753 4.509 −20.414 1.00 126.27 O ATOM 193 N SER A 432 −23.513 3.239 −21.050 1.00 112.47 N ATOM 194 CA SER A 432 −22.921 1.914 −20.795 1.00 114.55 C ATOM 195 C SER A 432 −22.923 1.605 −19.290 1.00 117.46 C ATOM 196 O SER A 432 −22.469 0.543 −18.855 1.00 120.57 O ATOM 197 CB SER A 432 −21.523 1.752 −21.418 1.00 112.91 C ATOM 198 OG SER A 432 −20.966 0.476 −21.134 1.00 110.75 O ATOM 199 N TYR A 433 −23.445 2.553 −18.512 1.00 113.77 N ATOM 200 CA TYR A 433 −23.690 2.386 −17.086 1.00 108.07 C ATOM 201 C TYR A 433 −25.099 2.887 −16.842 1.00 100.32 C ATOM 202 O TYR A 433 −25.743 2.541 −15.848 1.00 92.34 O ATOM 203 CB TYR A 433 −22.717 3.225 −16.257 1.00 114.16 C ATOM 204 CG TYR A 433 −21.526 3.750 −17.027 1.00 123.59 C ATOM 205 CD2 TYR A 433 −21.417 5.101 −17.343 1.00 121.36 C ATOM 206 CD1 TYR A 433 −20.500 2.897 −17.423 1.00 128.94 C ATOM 207 CE2 TYR A 433 −20.320 5.586 −18.043 1.00 125.82 C ATOM 208 CE1 TYR A 433 −19.406 3.370 −18.127 1.00 132.24 C ATOM 209 CZ TYR A 433 −19.319 4.712 −18.435 1.00 132.44 C ATOM 210 OH TYR A 433 −18.225 5.178 −19.133 1.00 139.72 O ATOM 211 N SER A 434 −25.563 3.714 −17.773 1.00 95.53 N ATOM 212 CA SER A 434 −26.863 4.355 −17.675 1.00 95.37 C ATOM 213 C SER A 434 −27.562 4.359 −19.025 1.00 93.72 C ATOM 214 O SER A 434 −26.923 4.409 −20.074 1.00 96.30 O ATOM 215 CB SER A 434 −26.702 5.801 −17.212 1.00 97.16 C ATOM 216 OG SER A 434 −26.126 6.589 −18.241 1.00 104.36 O ATOM 217 N VAL A 435 −28.886 4.311 −18.983 1.00 84.71 N ATOM 218 CA VAL A 435 −29.692 4.549 −20.162 1.00 76.32 C ATOM 219 C VAL A 435 −30.497 5.812 −19.896 1.00 68.29 C ATOM 220 O VAL A 435 −31.002 6.010 −18.790 1.00 62.06 O ATOM 221 CB VAL A 435 −30.650 3.378 −20.438 1.00 76.43 C ATOM 222 CG1 VAL A 435 −31.331 3.560 −21.790 1.00 80.88 C ATOM 223 CG2 VAL A 435 −29.901 2.062 −20.392 1.00 85.57 C ATOM 224 N CYS A 436 −30.586 6.682 −20.893 1.00 60.43 N ATOM 225 CA CYS A 436 −31.444 7.856 −20.798 1.00 55.26 C ATOM 226 C CYS A 436 −32.658 7.653 −21.704 1.00 60.74 C ATOM 227 O CYS A 436 −32.512 7.289 −22.873 1.00 69.02 O ATOM 228 CB CYS A 436 −30.673 9.128 −21.179 1.00 55.04 C ATOM 229 SG CYS A 436 −29.358 9.598 −20.011 1.00 71.96 S ATOM 230 N LYS A 437 −33.856 7.857 −21.162 1.00 51.36 N ATOM 231 CA LYS A 437 −35.077 7.704 −21.956 1.00 59.33 C ATOM 232 C LYS A 437 −35.978 8.929 −21.856 1.00 64.38 C ATOM 233 O LYS A 437 −35.846 9.745 −20.939 1.00 50.87 O ATOM 234 CB LYS A 437 −35.860 6.445 −21.554 1.00 59.09 C ATOM 235 CG LYS A 437 −35.125 5.137 −21.785 1.00 66.28 C ATOM 236 CD LYS A 437 −36.023 3.948 −21.480 1.00 79.01 C ATOM 237 CE LYS A 437 −35.224 2.655 −21.324 1.00 87.75 C ATOM 238 NZ LYS A 437 −34.439 2.320 −22.546 1.00 99.02 N ATOM 239 N ARG A 438 −36.878 9.067 −22.825 1.00 61.60 N ATOM 240 CA ARG A 438 −37.890 10.104 −22.767 1.00 54.91 C ATOM 241 C ARG A 438 −39.050 9.559 −21.958 1.00 59.97 C ATOM 242 O ARG A 438 −39.383 8.375 −22.057 1.00 59.81 O ATOM 243 CB ARG A 438 −38.373 10.474 −24.182 1.00 55.49 C ATOM 244 CG ARG A 438 −39.289 11.702 −24.215 1.00 54.37 C ATOM 245 CD ARG A 438 −39.628 12.148 −25.651 1.00 58.13 C ATOM 246 NE ARG A 438 −40.372 11.108 −26.355 1.00 68.81 N ATOM 247 CZ ARG A 438 −41.695 10.993 −26.336 1.00 69.10 C ATOM 248 NH1 ARG A 438 −42.428 11.874 −25.665 1.00 66.58 N ATOM 249 NH2 ARG A 438 −42.283 9.999 −26.990 1.00 65.48 N ATOM 250 N CYS A 439 −39.676 10.404 −21.152 1.00 50.98 N ATOM 251 CA CYS A 439 −40.852 9.942 −20.424 1.00 52.78 C ATOM 252 C CYS A 439 −41.964 10.978 −20.409 1.00 49.77 C ATOM 253 O CYS A 439 −41.746 12.156 −20.707 1.00 52.56 O ATOM 254 CB CYS A 439 −40.494 9.514 −18.987 1.00 44.44 C ATOM 255 SG CYS A 439 −39.621 10.747 −18.032 1.00 52.40 S ATOM 256 N ILE A 440 −43.158 10.518 −20.052 1.00 57.09 N ATOM 257 CA ILE A 440 −44.318 11.384 −19.948 1.00 58.28 C ATOM 258 C ILE A 440 −44.865 11.364 −18.533 1.00 59.77 C ATOM 259 O ILE A 440 −45.177 10.305 −17.982 1.00 60.90 O ATOM 260 CB ILE A 440 −45.431 10.957 −20.921 1.00 57.51 C ATOM 261 CG1 ILE A 440 −44.928 11.040 −22.364 1.00 58.48 C ATOM 262 CG2 ILE A 440 −46.674 11.820 −20.717 1.00 60.16 C ATOM 263 CD1 ILE A 440 −45.929 10.553 −23.391 1.00 70.13 C ATOM 264 N HIS A 441 −44.962 12.546 −17.943 1.00 58.16 N ATOM 265 CA HIS A 441 −45.571 12.705 −16.635 1.00 53.79 C ATOM 266 C HIS A 441 −47.088 12.582 −16.807 1.00 60.37 C ATOM 267 O HIS A 441 −47.714 13.405 −17.479 1.00 53.35 O ATOM 268 CB HIS A 441 −45.185 14.070 −16.066 1.00 52.16 C ATOM 269 CG HIS A 441 −45.691 14.323 −14.681 1.00 51.33 C ATOM 270 ND1 HIS A 441 −46.546 15.362 −14.379 1.00 59.37 N ATOM 271 CD2 HIS A 441 −45.463 13.673 −13.516 1.00 52.68 C ATOM 272 CE1 HIS A 441 −46.817 15.345 −13.088 1.00 67.68 C ATOM 273 NE2 HIS A 441 −46.169 14.333 −12.540 1.00 60.97 N ATOM 274 N LYS A 442 −47.668 11.542 −16.217 1.00 54.74 N ATOM 275 CA LYS A 442 −49.057 11.173 −16.500 1.00 60.99 C ATOM 276 C LYS A 442 −50.072 12.258 −16.139 1.00 67.21 C ATOM 277 O LYS A 442 −51.038 12.480 −16.865 1.00 68.41 O ATOM 278 CB LYS A 442 −49.419 9.859 −15.797 1.00 65.74 C ATOM 279 CG LYS A 442 −48.686 8.634 −16.323 1.00 72.12 C ATOM 280 CD LYS A 442 −49.151 7.372 −15.605 1.00 83.09 C ATOM 281 CE LYS A 442 −48.388 6.137 −16.063 1.00 85.39 C ATOM 282 NZ LYS A 442 −48.763 4.921 −15.285 1.00 86.32 N ATOM 283 N ALA A 443 −49.842 12.942 −15.024 1.00 61.15 N ATOM 284 CA ALA A 443 −50.805 13.923 −14.528 1.00 72.33 C ATOM 285 C ALA A 443 −50.882 15.210 −15.365 1.00 77.29 C ATOM 286 O ALA A 443 −51.799 16.019 −15.176 1.00 66.81 O ATOM 287 CB ALA A 443 −50.515 14.255 −13.062 1.00 71.67 C ATOM 288 N THR A 444 −49.930 15.402 −16.281 1.00 60.62 N ATOM 289 CA THR A 444 −49.833 16.664 −17.016 1.00 57.97 C ATOM 290 C THR A 444 −49.606 16.482 −18.515 1.00 58.96 C ATOM 291 O THR A 444 −49.828 17.412 −19.291 1.00 59.34 O ATOM 292 CB THR A 444 −48.678 17.540 −16.483 1.00 64.74 C ATOM 293 OG1 THR A 444 −47.433 16.863 −16.684 1.00 64.46 O ATOM 294 CG2 THR A 444 −48.859 17.840 −15.007 1.00 62.15 C ATOM 295 N ASN A 445 −49.170 15.283 −18.905 1.00 52.64 N ATOM 296 CA ASN A 445 −48.735 14.992 −20.277 1.00 54.81 C ATOM 297 C ASN A 445 −47.513 15.794 −20.742 1.00 57.65 C ATOM 298 O ASN A 445 −47.220 15.835 −21.935 1.00 57.93 O ATOM 299 CB ASN A 445 −49.894 15.099 −21.284 1.00 55.25 C ATOM 300 CG ASN A 445 −50.912 13.993 −21.107 1.00 64.89 C ATOM 301 OD1 ASN A 445 −50.552 12.821 −21.011 1.00 62.09 O ATOM 302 ND2 ASN A 445 −52.193 14.360 −21.050 1.00 65.82 N ATOM 303 N MET A 446 −46.802 16.411 −19.794 1.00 50.37 N ATOM 304 CA MET A 446 −45.534 17.083 −20.082 1.00 49.19 C ATOM 305 C MET A 446 −44.473 16.026 −20.297 1.00 52.80 C ATOM 306 O MET A 446 −44.559 14.941 −19.725 1.00 56.14 O ATOM 307 CB MET A 446 −45.086 17.939 −18.892 1.00 51.22 C ATOM 308 CG MET A 446 −45.887 19.199 −18.646 1.00 60.86 C ATOM 309 SD MET A 446 −45.083 20.278 −17.436 1.00 63.35 S ATOM 310 CE MET A 446 −43.496 20.535 −18.227 1.00 67.46 C ATOM 311 N GLU A 447 −43.439 16.340 −21.070 1.00 55.19 N ATOM 312 CA GLU A 447 −42.391 15.356 −21.267 1.00 47.79 C ATOM 313 C GLU A 447 −41.091 15.744 −20.582 1.00 59.74 C ATOM 314 O GLU A 447 −40.802 16.922 −20.390 1.00 55.30 O ATOM 315 CB GLU A 447 −42.179 15.031 −22.747 1.00 63.68 C ATOM 316 CG GLU A 447 −41.847 16.205 −23.623 1.00 75.17 C ATOM 317 CD GLU A 447 −41.925 15.853 −25.095 1.00 86.42 C ATOM 318 OE1 GLU A 447 −42.459 14.771 −25.426 1.00 92.85 O ATOM 319 OE2 GLU A 447 −41.449 16.656 −25.921 1.00 85.00 O ATOM 320 N PHE A 448 −40.321 14.725 −20.210 1.00 53.82 N ATOM 321 CA PHE A 448 −39.084 14.894 −19.465 1.00 43.61 C ATOM 322 C PHE A 448 −38.123 13.821 −19.915 1.00 51.93 C ATOM 323 O PHE A 448 −38.496 12.930 −20.681 1.00 56.07 O ATOM 324 CB PHE A 448 −39.342 14.725 −17.954 1.00 45.84 C ATOM 325 CG PHE A 448 −40.247 15.764 −17.381 1.00 45.48 C ATOM 326 CD2 PHE A 448 −41.601 15.508 −17.209 1.00 47.68 C ATOM 327 CD1 PHE A 448 −39.751 17.006 −17.026 1.00 48.85 C ATOM 328 CE2 PHE A 448 −42.444 16.475 −16.690 1.00 56.72 C ATOM 329 CE1 PHE A 448 −40.590 17.980 −16.508 1.00 45.35 C ATOM 330 CZ PHE A 448 −41.940 17.713 −16.340 1.00 47.55 C ATOM 331 N ALA A 449 −36.886 13.913 −19.430 1.00 45.79 N ATOM 332 CA ALA A 449 −35.896 12.879 −19.643 1.00 42.74 C ATOM 333 C ALA A 449 −35.719 12.126 −18.329 1.00 49.88 C ATOM 334 O ALA A 449 −35.834 12.712 −17.254 1.00 51.49 O ATOM 335 CB ALA A 449 −34.557 13.488 −20.082 1.00 39.71 C ATOM 336 N VAL A 450 −35.441 10.830 −18.418 1.00 50.99 N ATOM 337 CA VAL A 450 −35.091 10.059 −17.234 1.00 48.59 C ATOM 338 C VAL A 450 −33.782 9.306 −17.481 1.00 55.02 C ATOM 339 O VAL A 450 −33.621 8.650 −18.505 1.00 56.43 O ATOM 340 CB VAL A 450 −36.231 9.104 −16.810 1.00 59.91 C ATOM 341 CG1 VAL A 450 −36.601 8.142 −17.937 1.00 59.40 C ATOM 342 CG2 VAL A 450 −35.851 8.354 −15.540 1.00 60.84 C ATOM 343 N LYS A 451 −32.833 9.452 −16.563 1.00 55.75 N ATOM 344 CA LYS A 451 −31.585 8.693 −16.622 1.00 54.89 C ATOM 345 C LYS A 451 −31.744 7.527 −15.670 1.00 59.06 C ATOM 346 O LYS A 451 −32.024 7.715 −14.487 1.00 58.38 O ATOM 347 CB LYS A 451 −30.384 9.571 −16.234 1.00 49.98 C ATOM 348 CG LYS A 451 −29.023 8.861 −16.139 1.00 57.09 C ATOM 349 CD LYS A 451 −27.909 9.905 −16.036 1.00 55.25 C ATOM 350 CE LYS A 451 −26.530 9.295 −15.931 1.00 66.78 C ATOM 351 NZ LYS A 451 −25.481 10.367 −15.900 1.00 65.48 N ATOM 352 N ILE A 452 −31.612 6.318 −16.198 1.00 61.83 N ATOM 353 CA ILE A 452 −31.817 5.117 −15.404 1.00 61.31 C ATOM 354 C ILE A 452 −30.461 4.484 −15.106 1.00 60.73 C ATOM 355 O ILE A 452 −29.738 4.093 −16.022 1.00 61.90 O ATOM 356 CB ILE A 452 −32.724 4.120 −16.142 1.00 67.27 C ATOM 357 CG1 ILE A 452 −34.044 4.798 −16.529 1.00 66.46 C ATOM 358 CG2 ILE A 452 −32.973 2.890 −15.287 1.00 62.64 C ATOM 359 CD1 ILE A 452 −34.980 3.910 −17.310 1.00 74.38 C ATOM 360 N ILE A 453 −30.120 4.395 −13.822 1.00 66.39 N ATOM 361 CA ILE A 453 −28.763 4.036 −13.413 1.00 68.34 C ATOM 362 C ILE A 453 −28.690 2.705 −12.666 1.00 71.49 C ATOM 363 O ILE A 453 −29.328 2.521 −11.629 1.00 69.68 O ATOM 364 CB ILE A 453 −28.136 5.137 −12.536 1.00 64.85 C ATOM 365 CG1 ILE A 453 −28.179 6.485 −13.262 1.00 64.84 C ATOM 366 CG2 ILE A 453 −26.700 4.771 −12.161 1.00 71.83 C ATOM 367 CD1 ILE A 453 −27.822 7.652 −12.371 1.00 61.37 C ATOM 368 N ASP A 454 −27.893 1.785 −13.200 1.00 78.51 N ATOM 369 CA ASP A 454 −27.735 0.456 −12.619 1.00 77.54 C ATOM 370 C ASP A 454 −26.870 0.551 −11.363 1.00 75.79 C ATOM 371 O ASP A 454 −25.670 0.818 −11.444 1.00 74.79 O ATOM 372 CB ASP A 454 −27.082 −0.481 −13.645 1.00 83.82 C ATOM 373 CG ASP A 454 −27.346 −1.954 −13.360 1.00 91.61 C ATOM 374 OD1 ASP A 454 −27.494 −2.331 −12.175 1.00 92.56 O ATOM 375 OD2 ASP A 454 −27.398 −2.740 −14.332 1.00 89.93 O ATOM 376 N LYS A 455 −27.481 0.338 −10.202 1.00 74.78 N ATOM 377 CA LYS A 455 −26.773 0.454 −8.934 1.00 82.72 C ATOM 378 C LYS A 455 −25.659 −0.587 −8.811 1.00 89.08 C ATOM 379 O LYS A 455 −24.697 −0.389 −8.070 1.00 86.34 O ATOM 380 CB LYS A 455 −27.760 0.327 −7.772 1.00 83.92 C ATOM 381 CG LYS A 455 −28.996 1.186 −7.963 1.00 71.26 C ATOM 382 CD LYS A 455 −29.934 1.108 −6.768 1.00 81.16 C ATOM 383 CE LYS A 455 −29.306 1.742 −5.542 1.00 81.96 C ATOM 384 NZ LYS A 455 −30.214 1.679 −4.372 1.00 87.51 N ATOM 385 N SER A 456 −25.800 −1.688 −9.546 1.00 94.12 N ATOM 386 CA SER A 456 −24.789 −2.743 −9.583 1.00 94.31 C ATOM 387 C SER A 456 −23.486 −2.189 −10.125 1.00 91.92 C ATOM 388 O SER A 456 −22.404 −2.517 −9.639 1.00 95.44 O ATOM 389 CB SER A 456 −25.243 −3.880 −10.498 1.00 92.72 C ATOM 390 OG SER A 456 −26.595 −4.223 −10.259 1.00 98.18 O ATOM 391 N LYS A 457 −23.607 −1.340 −11.137 1.00 86.55 N ATOM 392 CA LYS A 457 −22.454 −0.831 −11.861 1.00 94.15 C ATOM 393 C LYS A 457 −21.993 0.529 −11.336 1.00 100.55 C ATOM 394 O LYS A 457 −20.807 0.850 −11.398 1.00 102.15 O ATOM 395 CB LYS A 457 −22.773 −0.768 −13.362 1.00 96.45 C ATOM 396 CG LYS A 457 −21.690 −0.141 −14.227 1.00 102.62 C ATOM 397 CD LYS A 457 −21.811 −0.589 −15.679 1.00 106.18 C ATOM 398 CE LYS A 457 −21.244 −1.992 −15.882 1.00 106.69 C ATOM 399 NZ LYS A 457 −19.756 −2.025 −15.781 1.00 105.49 N ATOM 400 N ARG A 458 −22.921 1.321 −10.803 1.00 101.66 N ATOM 401 CA ARG A 458 −22.589 2.680 −10.375 1.00 96.12 C ATOM 402 C ARG A 458 −23.343 3.163 −9.137 1.00 94.82 C ATOM 403 O ARG A 458 −24.507 2.824 −8.929 1.00 102.55 O ATOM 404 CB ARG A 458 −22.829 3.669 −11.516 1.00 89.09 C ATOM 405 CG ARG A 458 −21.679 4.625 −11.745 1.00 89.74 C ATOM 406 CD ARG A 458 −22.113 5.775 −12.620 1.00 96.43 C ATOM 407 NE ARG A 458 −22.638 6.874 −11.820 1.00 95.51 N ATOM 408 CZ ARG A 458 −23.518 7.766 −12.259 1.00 87.97 C ATOM 409 NH1 ARG A 458 −23.994 7.687 −13.497 1.00 93.08 N ATOM 410 NH2 ARG A 458 −23.927 8.732 −11.452 1.00 81.58 N ATOM 411 N ASP A 459 −22.664 3.967 −8.323 1.00 82.22 N ATOM 412 CA ASP A 459 −23.292 4.636 −7.188 1.00 77.58 C ATOM 413 C ASP A 459 −23.530 6.103 −7.540 1.00 71.42 C ATOM 414 O ASP A 459 −22.588 6.898 −7.585 1.00 65.83 O ATOM 415 CB ASP A 459 −22.407 4.531 −5.948 1.00 88.42 C ATOM 416 CG ASP A 459 −22.831 5.484 −4.850 1.00 104.95 C ATOM 417 OD2 ASP A 459 −21.943 6.015 −4.150 1.00 114.81 O ATOM 418 OD1 ASP A 459 −24.051 5.708 −4.684 1.00 107.23 O ATOM 419 N PRO A 460 −24.795 6.470 −7.788 1.00 71.37 N ATOM 420 CA PRO A 460 −25.107 7.806 −8.301 1.00 70.59 C ATOM 421 C PRO A 460 −25.310 8.842 −7.203 1.00 70.26 C ATOM 422 O PRO A 460 −25.804 9.931 −7.497 1.00 66.16 O ATOM 423 CB PRO A 460 −26.432 7.592 −9.044 1.00 80.09 C ATOM 424 CG PRO A 460 −26.894 6.186 −8.689 1.00 84.98 C ATOM 425 CD PRO A 460 −26.015 5.676 −7.593 1.00 83.22 C ATOM 426 N THR A 461 −24.935 8.513 −5.971 1.00 69.86 N ATOM 427 CA THR A 461 −25.155 9.411 −4.840 1.00 68.13 C ATOM 428 C THR A 461 −24.556 10.803 −5.085 1.00 65.89 C ATOM 429 O THR A 461 −25.250 11.812 −4.950 1.00 57.94 O ATOM 430 CB THR A 461 −24.649 8.792 −3.524 1.00 72.44 C ATOM 431 OG1 THR A 461 −25.398 7.598 −3.256 1.00 75.61 O ATOM 432 CG2 THR A 461 −24.833 9.763 −2.354 1.00 68.03 C ATOM 433 N GLU A 462 −23.288 10.848 −5.482 1.00 60.65 N ATOM 434 CA GLU A 462 −22.614 12.106 −5.801 1.00 66.55 C ATOM 435 C GLU A 462 −23.362 12.917 −6.860 1.00 68.97 C ATOM 436 O GLU A 462 −23.633 14.119 −6.685 1.00 55.09 O ATOM 437 CB GLU A 462 −21.197 11.824 −6.289 1.00 70.12 C ATOM 438 CG GLU A 462 −20.353 13.058 −6.469 1.00 62.35 C ATOM 439 CD GLU A 462 −19.641 13.476 −5.195 1.00 72.12 C ATOM 440 OE1 GLU A 462 −20.296 13.581 −4.138 1.00 83.00 O ATOM 441 OE2 GLU A 462 −18.415 13.696 −5.251 1.00 81.98 O ATOM 442 N GLU A 463 −23.696 12.257 −7.961 1.00 60.55 N ATOM 443 CA GLU A 463 −24.376 12.922 −9.050 1.00 52.65 C ATOM 444 C GLU A 463 −25.707 13.502 −8.597 1.00 48.90 C ATOM 445 O GLU A 463 −26.054 14.643 −8.928 1.00 52.09 O ATOM 446 CB GLU A 463 −24.606 11.956 −10.208 1.00 51.77 C ATOM 447 CG GLU A 463 −25.390 12.595 −11.362 1.00 52.72 C ATOM 448 CD GLU A 463 −25.436 11.712 −12.586 1.00 56.33 C ATOM 449 OE1 GLU A 463 −25.053 10.525 −12.476 1.00 63.63 O ATOM 450 OE2 GLU A 463 −25.838 12.201 −13.660 1.00 53.95 O ATOM 451 N ILE A 464 −26.461 12.722 −7.833 1.00 48.69 N ATOM 452 CA ILE A 464 −27.773 13.190 −7.385 1.00 50.41 C ATOM 453 C ILE A 464 −27.647 14.338 −6.379 1.00 58.61 C ATOM 454 O ILE A 464 −28.420 15.298 −6.440 1.00 49.15 O ATOM 455 CB ILE A 464 −28.620 12.027 −6.813 1.00 57.14 C ATOM 456 CG1 ILE A 464 −28.946 11.027 −7.928 1.00 63.03 C ATOM 457 CG2 ILE A 464 −29.907 12.536 −6.161 1.00 56.16 C ATOM 458 CD1 ILE A 464 −29.321 9.659 −7.407 1.00 74.54 C ATOM 459 N GLU A 465 −26.666 14.259 −5.473 1.00 54.90 N ATOM 460 CA GLU A 465 −26.466 15.333 −4.490 1.00 50.87 C ATOM 461 C GLU A 465 −26.150 16.661 −5.176 1.00 48.57 C ATOM 462 O GLU A 465 −26.665 17.709 −4.773 1.00 48.92 O ATOM 463 CB GLU A 465 −25.355 14.986 −3.487 1.00 54.40 C ATOM 464 CG GLU A 465 −25.791 14.129 −2.314 1.00 63.82 C ATOM 465 CD GLU A 465 −24.655 13.847 −1.339 0.49 76.57 C ATOM 466 OE1 GLU A 465 −24.908 13.180 −0.312 0.92 90.73 O ATOM 467 OE2 GLU A 465 −23.509 14.286 −1.598 1.00 70.74 O ATOM 468 N ILE A 466 −25.303 16.610 −6.204 1.00 47.17 N ATOM 469 CA ILE A 466 −24.967 17.803 −6.998 1.00 48.23 C ATOM 470 C ILE A 466 −26.171 18.383 −7.723 1.00 53.44 C ATOM 471 O ILE A 466 −26.426 19.598 −7.671 1.00 51.83 O ATOM 472 CB ILE A 466 −23.840 17.509 −8.008 1.00 52.07 C ATOM 473 CG1 ILE A 466 −22.541 17.225 −7.245 1.00 62.18 C ATOM 474 CG2 ILE A 466 −23.681 18.674 −9.005 1.00 47.93 C ATOM 475 CD1 ILE A 466 −21.428 16.644 −8.110 1.00 53.91 C ATOM 476 N LEU A 467 −26.913 17.526 −8.411 1.00 47.25 N ATOM 477 CA LEU A 467 −28.133 17.988 −9.079 1.00 52.09 C ATOM 478 C LEU A 467 −29.155 18.583 −8.118 1.00 50.45 C ATOM 479 O LEU A 467 −29.789 19.608 −8.421 1.00 43.92 O ATOM 480 CB LEU A 467 −28.755 16.855 −9.899 1.00 47.63 C ATOM 481 CG LEU A 467 −27.864 16.451 −11.080 1.00 52.32 C ATOM 482 CD1 LEU A 467 −28.375 15.177 −11.733 1.00 59.11 C ATOM 483 CD2 LEU A 467 −27.769 17.595 −12.109 1.00 44.29 C ATOM 484 N LEU A 468 −29.329 17.943 −6.963 1.00 48.34 N ATOM 485 CA LEU A 468 −30.285 18.424 −5.967 1.00 52.39 C ATOM 486 C LEU A 468 −29.873 19.784 −5.436 1.00 61.76 C ATOM 487 O LEU A 468 −30.702 20.649 −5.194 1.00 52.52 O ATOM 488 CB LEU A 468 −30.361 17.452 −4.782 1.00 55.16 C ATOM 489 CG LEU A 468 −31.263 16.235 −4.932 1.00 57.96 C ATOM 490 CD1 LEU A 468 −31.004 15.231 −3.816 1.00 63.91 C ATOM 491 CD2 LEU A 468 −32.720 16.684 −4.925 1.00 58.07 C ATOM 492 N ARG A 469 −28.574 19.955 −5.235 1.00 50.11 N ATOM 493 CA ARG A 469 −28.065 21.151 −4.603 1.00 56.51 C ATOM 494 C ARG A 469 −27.933 22.305 −5.599 1.00 50.64 C ATOM 495 O ARG A 469 −28.168 23.463 −5.249 1.00 55.06 O ATOM 496 CB ARG A 469 −26.723 20.810 −3.953 1.00 57.11 C ATOM 497 CG ARG A 469 −25.930 21.963 −3.416 1.00 69.90 C ATOM 498 CD ARG A 469 −26.675 22.816 −2.438 0.81 74.27 C ATOM 499 NE ARG A 469 −25.755 23.626 −1.644 1.00 72.10 N ATOM 500 CZ ARG A 469 −25.642 23.525 −0.325 0.60 82.44 C ATOM 501 NH1 ARG A 469 −26.398 22.651 0.324 1.00 77.85 N ATOM 502 NH2 ARG A 469 −24.786 24.291 0.341 1.00 82.68 N ATOM 503 N TYR A 470 −27.577 21.994 −6.842 1.00 46.40 N ATOM 504 CA TYR A 470 −27.164 23.045 −7.776 1.00 44.03 C ATOM 505 C TYR A 470 −28.002 23.108 −9.055 1.00 46.92 C ATOM 506 O TYR A 470 −27.820 24.005 −9.869 1.00 52.37 O ATOM 507 CB TYR A 470 −25.673 22.886 −8.129 1.00 45.04 C ATOM 508 CG TYR A 470 −24.751 22.817 −6.915 1.00 51.79 C ATOM 509 CD1 TYR A 470 −24.536 23.934 −6.112 1.00 57.95 C ATOM 510 CD2 TYR A 470 −24.082 21.638 −6.585 1.00 43.71 C ATOM 511 CE1 TYR A 470 −23.692 23.882 −4.997 1.00 63.92 C ATOM 512 CE2 TYR A 470 −23.235 21.576 −5.465 1.00 48.30 C ATOM 513 CZ TYR A 470 −23.042 22.702 −4.680 1.00 65.52 C ATOM 514 OH TYR A 470 −22.210 22.645 −3.567 1.00 61.32 O ATOM 515 N GLY A 471 −28.931 22.172 −9.217 1.00 50.89 N ATOM 516 CA GLY A 471 −29.740 22.097 −10.424 1.00 50.86 C ATOM 517 C GLY A 471 −30.671 23.275 −10.582 1.00 49.87 C ATOM 518 O GLY A 471 −31.245 23.495 −11.649 1.00 45.60 O ATOM 519 N GLN A 472 −30.839 24.039 −9.510 1.00 41.16 N ATOM 520 CA GLN A 472 −31.718 25.196 −9.561 1.00 50.99 C ATOM 521 C GLN A 472 −31.034 26.369 −10.282 1.00 43.25 C ATOM 522 O GLN A 472 −31.676 27.371 −10.599 1.00 44.06 O ATOM 523 CB GLN A 472 −32.145 25.586 −8.144 1.00 62.29 C ATOM 524 CG GLN A 472 −33.624 25.774 −7.993 1.00 79.77 C ATOM 525 CD GLN A 472 −33.980 27.228 −7.961 1.00 89.01 C ATOM 526 OE1 GLN A 472 −33.100 28.084 −8.049 0.46 92.48 O ATOM 527 NE2 GLN A 472 −35.266 27.527 −7.827 1.00 86.85 N ATOM 528 N HIS A 473 −29.727 26.247 −10.516 1.00 39.97 N ATOM 529 CA HIS A 473 −29.030 27.225 −11.340 1.00 43.28 C ATOM 530 C HIS A 473 −29.716 27.260 −12.706 1.00 42.87 C ATOM 531 O HIS A 473 −30.001 26.208 −13.281 1.00 38.41 O ATOM 532 CB HIS A 473 −27.553 26.838 −11.492 1.00 39.48 C ATOM 533 CG HIS A 473 −26.704 27.925 −12.079 1.00 48.46 C ATOM 534 ND1 HIS A 473 −26.778 28.295 −13.407 1.00 43.36 N ATOM 535 CD2 HIS A 473 −25.784 28.742 −11.511 1.00 47.22 C ATOM 536 CE1 HIS A 473 −25.928 29.284 −13.632 1.00 46.09 C ATOM 537 NE2 HIS A 473 −25.320 29.579 −12.497 1.00 47.66 N ATOM 538 N PRO A 474 −29.997 28.467 −13.223 1.00 45.01 N ATOM 539 CA PRO A 474 −30.657 28.620 −14.528 1.00 49.68 C ATOM 540 C PRO A 474 −29.984 27.880 −15.677 1.00 39.78 C ATOM 541 O PRO A 474 −30.659 27.488 −16.631 1.00 39.20 O ATOM 542 CB PRO A 474 −30.597 30.130 −14.782 1.00 48.62 C ATOM 543 CG PRO A 474 −29.558 30.650 −13.846 1.00 59.65 C ATOM 544 CD PRO A 474 −29.664 29.774 −12.632 1.00 50.42 C ATOM 545 N ASN A 475 −28.675 27.689 −15.610 1.00 40.34 N ATOM 546 CA ASN A 475 −27.974 27.087 −16.744 1.00 36.71 C ATOM 547 C ASN A 475 −27.396 25.716 −16.422 1.00 42.93 C ATOM 548 O ASN A 475 −26.477 25.254 −17.090 1.00 41.20 O ATOM 549 CB ASN A 475 −26.872 28.042 −17.230 1.00 35.01 C ATOM 550 CG ASN A 475 −27.443 29.376 −17.726 1.00 38.36 C ATOM 551 OD1 ASN A 475 −27.277 30.413 −17.082 1.00 40.20 O ATOM 552 ND2 ASN A 475 −28.112 29.343 −18.872 1.00 39.98 N ATOM 553 N ILE A 476 −27.914 25.084 −15.375 1.00 40.72 N ATOM 554 CA ILE A 476 −27.533 23.709 −15.064 1.00 39.99 C ATOM 555 C ILE A 476 −28.795 22.905 −15.285 1.00 42.96 C ATOM 556 O ILE A 476 −29.872 23.399 −15.002 1.00 38.88 O ATOM 557 CB ILE A 476 −27.049 23.565 −13.597 1.00 37.95 C ATOM 558 CG1 ILE A 476 −25.664 24.220 −13.435 1.00 35.69 C ATOM 559 CG2 ILE A 476 −26.984 22.081 −13.176 1.00 38.69 C ATOM 560 CD1 ILE A 476 −25.140 24.226 −11.984 1.00 37.93 C ATOM 561 N ILE A 477 −28.677 21.689 −15.813 1.00 39.45 N ATOM 562 CA ILE A 477 −29.857 20.859 −16.058 1.00 43.04 C ATOM 563 C ILE A 477 −30.676 20.676 −14.768 1.00 38.05 C ATOM 564 O ILE A 477 −30.127 20.381 −13.718 1.00 41.98 O ATOM 565 CB ILE A 477 −29.475 19.491 −16.664 1.00 42.65 C ATOM 566 CG1 ILE A 477 −30.743 18.678 −16.947 1.00 48.52 C ATOM 567 CG2 ILE A 477 −28.497 18.757 −15.746 1.00 42.13 C ATOM 568 CD1 ILE A 477 −30.566 17.552 −17.922 1.00 53.26 C ATOM 569 N THR A 478 −31.987 20.887 −14.845 1.00 42.06 N ATOM 570 CA THR A 478 −32.801 20.930 −13.640 1.00 43.17 C ATOM 571 C THR A 478 −33.378 19.560 −13.308 1.00 45.99 C ATOM 572 O THR A 478 −33.995 18.911 −14.151 1.00 45.38 O ATOM 573 CB THR A 478 −33.955 21.945 −13.822 1.00 41.75 C ATOM 574 OG1 THR A 478 −33.418 23.178 −14.322 1.00 48.64 O ATOM 575 CG2 THR A 478 −34.676 22.197 −12.511 1.00 46.58 C ATOM 576 N LEU A 479 −33.172 19.123 −12.075 1.00 43.86 N ATOM 577 CA LEU A 479 −33.709 17.856 −11.600 1.00 41.82 C ATOM 578 C LEU A 479 −35.194 18.035 −11.297 1.00 48.73 C ATOM 579 O LEU A 479 −35.594 19.035 −10.700 1.00 51.65 O ATOM 580 CB LEU A 479 −32.954 17.425 −10.334 1.00 43.94 C ATOM 581 CG LEU A 479 −33.328 16.102 −9.672 1.00 58.09 C ATOM 582 CD1 LEU A 479 −33.002 14.960 −10.600 1.00 58.82 C ATOM 583 CD2 LEU A 479 −32.585 15.947 −8.349 1.00 64.71 C ATOM 584 N LYS A 480 −36.018 17.079 −11.718 1.00 46.92 N ATOM 585 CA LYS A 480 −37.466 17.191 −11.536 1.00 48.73 C ATOM 586 C LYS A 480 −37.980 16.129 −10.580 1.00 53.19 C ATOM 587 O LYS A 480 −38.898 16.377 −9.795 1.00 59.82 O ATOM 588 CB LYS A 480 −38.190 17.086 −12.883 1.00 55.66 C ATOM 589 CG LYS A 480 −37.857 18.210 −13.861 1.00 57.07 C ATOM 590 CD LYS A 480 −38.345 19.547 −13.329 1.00 69.87 C ATOM 591 CE LYS A 480 −38.040 20.684 −14.283 1.00 67.88 C ATOM 592 NZ LYS A 480 −38.851 21.891 −13.950 1.00 64.50 N ATOM 593 N ASP A 481 −37.375 14.947 −10.625 1.00 51.81 N ATOM 594 CA ASP A 481 −37.831 13.840 −9.784 1.00 52.35 C ATOM 595 C ASP A 481 −36.746 12.777 −9.673 1.00 55.41 C ATOM 596 O ASP A 481 −35.905 12.665 −10.562 1.00 52.69 O ATOM 597 CB ASP A 481 −39.093 13.223 −10.390 1.00 54.32 C ATOM 598 CG ASP A 481 −40.073 12.766 −9.347 1.00 73.81 C ATOM 599 OD2 ASP A 481 −41.281 12.716 −9.663 1.00 73.53 O ATOM 600 OD1 ASP A 481 −39.640 12.456 −8.217 1.00 85.58 O ATOM 601 N VAL A 482 −36.749 12.020 −8.571 1.00 60.38 N ATOM 602 CA VAL A 482 −35.809 10.903 −8.397 1.00 67.21 C ATOM 603 C VAL A 482 −36.476 9.705 −7.750 1.00 56.10 C ATOM 604 O VAL A 482 −37.225 9.855 −6.792 1.00 59.10 O ATOM 605 CB VAL A 482 −34.584 11.249 −7.511 1.00 69.73 C ATOM 606 CG1 VAL A 482 −33.476 10.226 −7.737 1.00 72.17 C ATOM 607 CG2 VAL A 482 −34.060 12.634 −7.807 1.00 57.40 C ATOM 608 N TYR A 483 −36.195 8.514 −8.269 1.00 67.98 N ATOM 609 CA TYR A 483 −36.724 7.280 −7.686 1.00 71.55 C ATOM 610 C TYR A 483 −35.618 6.246 −7.519 1.00 69.96 C ATOM 611 O TYR A 483 −34.660 6.226 −8.291 1.00 62.86 O ATOM 612 CB TYR A 483 −37.826 6.689 −8.568 1.00 71.50 C ATOM 613 CG TYR A 483 −39.048 7.562 −8.711 1.00 64.53 C ATOM 614 CD2 TYR A 483 −40.203 7.292 −7.995 1.00 68.30 C ATOM 615 CD1 TYR A 483 −39.049 8.653 −9.576 1.00 72.47 C ATOM 616 CE2 TYR A 483 −41.328 8.088 −8.129 1.00 76.04 C ATOM 617 CE1 TYR A 483 −40.165 9.454 −9.715 1.00 65.74 C ATOM 618 CZ TYR A 483 −41.299 9.167 −8.995 1.00 73.06 C ATOM 619 OH TYR A 483 −42.405 9.967 −9.141 1.00 78.92 O ATOM 620 N ASP A 484 −35.771 5.384 −6.516 1.00 71.80 N ATOM 621 CA ASP A 484 −34.839 4.282 −6.265 1.00 75.00 C ATOM 622 C ASP A 484 −35.664 3.047 −5.924 1.00 78.32 C ATOM 623 O ASP A 484 −36.348 3.023 −4.902 1.00 80.96 O ATOM 624 CB ASP A 484 −33.897 4.635 −5.102 1.00 84.63 C ATOM 625 CG ASP A 484 −32.790 3.593 −4.882 1.00 86.73 C ATOM 626 OD1 ASP A 484 −33.068 2.375 −4.909 1.00 82.15 O ATOM 627 OD2 ASP A 484 −31.624 3.999 −4.675 1.00 85.87 O ATOM 628 N ASP A 485 −35.612 2.027 −6.778 1.00 80.31 N ATOM 629 CA ASP A 485 −36.388 0.808 −6.546 1.00 92.15 C ATOM 630 C ASP A 485 −35.536 −0.312 −5.949 1.00 92.91 C ATOM 631 O ASP A 485 −35.969 −1.462 −5.874 1.00 98.29 O ATOM 632 CB ASP A 485 −37.107 0.345 −7.827 1.00 98.54 C ATOM 633 CG ASP A 485 −36.152 −0.107 −8.926 1.00 99.27 C ATOM 634 OD1 ASP A 485 −34.920 −0.014 −8.749 1.00 106.70 O ATOM 635 OD2 ASP A 485 −36.645 −0.551 −9.986 1.00 94.46 O ATOM 636 N GLY A 486 −34.326 0.042 −5.525 1.00 81.70 N ATOM 637 CA GLY A 486 −33.403 −0.913 −4.937 1.00 90.27 C ATOM 638 C GLY A 486 −32.407 −1.457 −5.945 1.00 102.70 C ATOM 639 O GLY A 486 −31.321 −1.907 −5.575 1.00 107.24 O ATOM 640 N LYS A 487 −32.777 −1.396 −7.223 1.00 94.67 N ATOM 641 CA LYS A 487 −31.996 −1.998 −8.299 1.00 88.63 C ATOM 642 C LYS A 487 −31.520 −0.918 −9.264 1.00 90.58 C ATOM 643 O LYS A 487 −30.413 −0.982 −9.814 1.00 84.16 O ATOM 644 CB LYS A 487 −32.865 −3.021 −9.033 1.00 101.52 C ATOM 645 CG LYS A 487 −32.106 −4.084 −9.808 1.00 109.57 C ATOM 646 CD LYS A 487 −33.037 −5.234 −10.190 1.00 114.84 C ATOM 647 CE LYS A 487 −34.361 −4.719 −10.746 1.00 116.43 C ATOM 648 NZ LYS A 487 −35.169 −5.804 −11.363 1.00 119.11 N ATOM 649 N TYR A 488 −32.368 0.085 −9.455 1.00 85.44 N ATOM 650 CA TYR A 488 −32.056 1.204 −10.333 1.00 84.35 C ATOM 651 C TYR A 488 −32.425 2.521 −9.684 1.00 77.33 C ATOM 652 O TYR A 488 −33.377 2.605 −8.907 1.00 79.24 O ATOM 653 CB TYR A 488 −32.825 1.092 −11.649 1.00 78.92 C ATOM 654 CG TYR A 488 −32.504 −0.130 −12.469 1.00 77.26 C ATOM 655 CD2 TYR A 488 −33.306 −1.263 −12.404 1.00 74.50 C ATOM 656 CD1 TYR A 488 −31.409 −0.146 −13.321 1.00 78.85 C ATOM 657 CE2 TYR A 488 −33.020 −2.380 −13.157 1.00 82.19 C ATOM 658 CE1 TYR A 488 −31.115 −1.260 −14.080 1.00 83.30 C ATOM 659 CZ TYR A 488 −31.923 −2.372 −13.995 1.00 84.09 C ATOM 660 OH TYR A 488 −31.633 −3.480 −14.750 1.00 96.40 O ATOM 661 N VAL A 489 −31.669 3.558 −10.016 1.00 79.97 N ATOM 662 CA VAL A 489 −32.059 4.903 −9.644 1.00 76.44 C ATOM 663 C VAL A 489 −32.621 5.601 −10.882 1.00 65.93 C ATOM 664 O VAL A 489 −32.016 5.562 −11.949 1.00 59.53 O ATOM 665 CB VAL A 489 −30.877 5.696 −9.073 1.00 78.01 C ATOM 666 CG1 VAL A 489 −31.376 6.959 −8.402 1.00 81.11 C ATOM 667 CG2 VAL A 489 −30.109 4.840 −8.078 1.00 77.45 C ATOM 668 N TYR A 490 −33.792 6.212 −10.745 1.00 66.59 N ATOM 669 CA TYR A 490 −34.398 6.942 −11.862 1.00 59.90 C ATOM 670 C TYR A 490 −34.275 8.433 −11.615 1.00 52.54 C ATOM 671 O TYR A 490 −34.881 8.968 −10.695 1.00 57.84 O ATOM 672 CB TYR A 490 −35.874 6.550 −12.040 1.00 63.28 C ATOM 673 CG TYR A 490 −36.072 5.065 −12.267 1.00 75.15 C ATOM 674 CD1 TYR A 490 −36.005 4.167 −11.207 1.00 83.38 C ATOM 675 CD2 TYR A 490 −36.305 4.559 −13.539 1.00 72.60 C ATOM 676 CE1 TYR A 490 −36.171 2.806 −11.405 1.00 91.85 C ATOM 677 CE2 TYR A 490 −36.476 3.198 −13.748 1.00 77.55 C ATOM 678 CZ TYR A 490 −36.406 2.325 −12.675 1.00 90.48 C ATOM 679 OH TYR A 490 −36.575 0.968 −12.867 1.00 88.94 O ATOM 680 N VAL A 491 −33.479 9.097 −12.439 1.00 50.54 N ATOM 681 CA VAL A 491 −33.250 10.527 −12.304 1.00 48.91 C ATOM 682 C VAL A 491 −34.014 11.295 −13.394 1.00 45.41 C ATOM 683 O VAL A 491 −33.634 11.257 −14.566 1.00 51.80 O ATOM 684 CB VAL A 491 −31.746 10.825 −12.412 1.00 50.49 C ATOM 685 CG1 VAL A 491 −31.482 12.317 −12.298 1.00 46.86 C ATOM 686 CG2 VAL A 491 −30.983 10.047 −11.347 1.00 61.41 C ATOM 687 N VAL A 492 −35.099 11.966 −13.013 1.00 48.62 N ATOM 688 CA VAL A 492 −35.911 12.683 −13.991 1.00 50.81 C ATOM 689 C VAL A 492 −35.501 14.146 −14.073 1.00 50.74 C ATOM 690 O VAL A 492 −35.442 14.842 −13.049 1.00 50.26 O ATOM 691 CB VAL A 492 −37.414 12.608 −13.646 1.00 56.70 C ATOM 692 CG1 VAL A 492 −38.245 13.147 −14.812 1.00 47.88 C ATOM 693 CG2 VAL A 492 −37.807 11.183 −13.310 1.00 52.04 C ATOM 694 N THR A 493 −35.216 14.610 −15.287 1.00 43.88 N ATOM 695 CA THR A 493 −34.808 15.996 −15.504 1.00 48.36 C ATOM 696 C THR A 493 −35.568 16.653 −16.641 1.00 50.05 C ATOM 697 O THR A 493 −36.340 16.001 −17.344 1.00 46.86 O ATOM 698 CB THR A 493 −33.321 16.091 −15.862 1.00 51.29 C ATOM 699 OG1 THR A 493 −33.123 15.647 −17.214 1.00 48.07 O ATOM 700 CG2 THR A 493 −32.484 15.249 −14.895 1.00 44.37 C ATOM 701 N GLU A 494 −35.356 17.951 −16.825 1.00 45.27 N ATOM 702 CA GLU A 494 −35.906 18.599 −18.010 1.00 54.57 C ATOM 703 C GLU A 494 −35.299 17.927 −19.241 1.00 41.67 C ATOM 704 O GLU A 494 −34.154 17.448 −19.206 1.00 44.74 O ATOM 705 CB GLU A 494 −35.661 20.116 −18.013 1.00 54.80 C ATOM 706 CG GLU A 494 −34.266 20.548 −17.596 1.00 60.23 C ATOM 707 CD GLU A 494 −34.131 22.062 −17.513 1.00 60.87 C ATOM 708 OE1 GLU A 494 −35.121 22.759 −17.819 1.00 48.52 O ATOM 709 OE2 GLU A 494 −33.040 22.562 −17.145 1.00 43.04 O ATOM 710 N LEU A 495 −36.114 17.833 −20.288 1.00 44.34 N ATOM 711 CA LEU A 495 −35.732 17.240 −21.564 1.00 52.01 C ATOM 712 C LEU A 495 −35.170 18.333 −22.474 1.00 49.14 C ATOM 713 O LEU A 495 −35.839 19.327 −22.737 1.00 41.11 O ATOM 714 CB LEU A 495 −36.969 16.618 −22.222 1.00 53.75 C ATOM 715 CG LEU A 495 −36.813 15.930 −23.579 1.00 49.77 C ATOM 716 CD1 LEU A 495 −35.921 14.714 −23.445 1.00 52.36 C ATOM 717 CD2 LEU A 495 −38.175 15.545 −24.152 1.00 45.56 C ATOM 718 N MET A 496 −33.940 18.160 −22.936 1.00 43.99 N ATOM 719 CA MET A 496 −33.329 19.135 −23.819 1.00 46.37 C ATOM 720 C MET A 496 −33.924 18.948 −25.206 1.00 57.98 C ATOM 721 O MET A 496 −33.797 17.879 −25.809 1.00 54.49 O ATOM 722 CB MET A 496 −31.813 18.932 −23.905 1.00 40.46 C ATOM 723 CG MET A 496 −31.060 19.087 −22.581 1.00 56.19 C ATOM 724 SD MET A 496 −31.337 20.682 −21.779 1.00 48.97 S ATOM 725 CE MET A 496 −32.293 20.107 −20.397 1.00 57.78 C ATOM 726 N LYS A 497 −34.585 19.975 −25.714 1.00 40.94 N ATOM 727 CA LYS A 497 −35.167 19.860 −27.047 1.00 45.17 C ATOM 728 C LYS A 497 −34.495 20.737 −28.113 1.00 49.87 C ATOM 729 O LYS A 497 −34.962 20.807 −29.250 1.00 50.66 O ATOM 730 CB LYS A 497 −36.675 20.099 −26.970 1.00 56.71 C ATOM 731 CG LYS A 497 −37.398 18.916 −26.346 1.00 55.20 C ATOM 732 CD LYS A 497 −38.627 19.340 −25.593 1.00 70.78 C ATOM 733 CE LYS A 497 −39.857 19.274 −26.456 1.00 80.50 C ATOM 734 NZ LYS A 497 −41.051 19.011 −25.602 1.00 73.66 N ATOM 735 N GLY A 498 −33.386 21.384 −27.762 1.00 39.67 N ATOM 736 CA GLY A 498 −32.716 22.262 −28.716 1.00 45.22 C ATOM 737 C GLY A 498 −31.396 21.703 −29.239 1.00 44.27 C ATOM 738 O GLY A 498 −30.691 22.370 −29.983 1.00 46.01 O ATOM 739 N GLY A 499 −31.053 20.490 −28.829 1.00 41.63 N ATOM 740 CA GLY A 499 −29.872 19.821 −29.350 1.00 47.76 C ATOM 741 C GLY A 499 −28.587 20.297 −28.699 1.00 45.86 C ATOM 742 O GLY A 499 −28.606 21.118 −27.771 1.00 47.81 O ATOM 743 N GLU A 500 −27.467 19.748 −29.161 1.00 43.83 N ATOM 744 CA GLU A 500 −26.159 20.146 −28.669 1.00 39.42 C ATOM 745 C GLU A 500 −25.818 21.560 −29.142 1.00 39.03 C ATOM 746 O GLU A 500 −26.126 21.945 −30.266 1.00 41.02 O ATOM 747 CB GLU A 500 −25.076 19.146 −29.104 1.00 50.27 C ATOM 748 CG GLU A 500 −25.262 17.730 −28.529 1.00 57.75 C ATOM 749 CD GLU A 500 −24.260 16.704 −29.076 1.00 65.28 C ATOM 750 OE1 GLU A 500 −23.227 17.095 −29.673 1.00 59.91 O ATOM 751 OE2 GLU A 500 −24.510 15.491 −28.906 1.00 57.79 O ATOM 752 N LEU A 501 −25.137 22.313 −28.283 1.00 38.16 N ATOM 753 CA LEU A 501 −24.861 23.719 −28.532 1.00 41.41 C ATOM 754 C LEU A 501 −24.048 23.854 −29.794 1.00 46.27 C ATOM 755 O LEU A 501 −24.397 24.605 −30.707 1.00 40.55 O ATOM 756 CB LEU A 501 −24.054 24.294 −27.361 1.00 47.68 C ATOM 757 CG LEU A 501 −23.764 25.793 −27.409 1.00 50.83 C ATOM 758 CD1 LEU A 501 −24.726 26.543 −26.518 1.00 47.57 C ATOM 759 CD2 LEU A 501 −22.318 26.081 −27.012 1.00 50.02 C ATOM 760 N LEU A 502 −22.969 23.092 −29.854 1.00 47.06 N ATOM 761 CA LEU A 502 −22.070 23.155 −30.994 1.00 61.68 C ATOM 762 C LEU A 502 −22.771 22.814 −32.299 1.00 57.22 C ATOM 763 O LEU A 502 −22.587 23.491 −33.308 1.00 65.34 O ATOM 764 CB LEU A 502 −20.880 22.226 −30.760 1.00 60.29 C ATOM 765 CG LEU A 502 −19.557 22.750 −31.285 1.00 49.20 C ATOM 766 CD1 LEU A 502 −19.431 24.233 −30.970 1.00 39.55 C ATOM 767 CD2 LEU A 502 −18.436 21.930 −30.685 1.00 39.02 C ATOM 768 N ASP A 503 −23.590 21.770 −32.281 1.00 50.82 N ATOM 769 CA ASP A 503 −24.339 21.383 −33.461 1.00 58.10 C ATOM 770 C ASP A 503 −25.160 22.534 −34.017 1.00 62.01 C ATOM 771 O ASP A 503 −25.243 22.722 −35.225 1.00 57.67 O ATOM 772 CB ASP A 503 −25.254 20.198 −33.156 1.00 70.69 C ATOM 773 CG ASP A 503 −24.754 18.905 −33.766 1.00 84.33 C ATOM 774 OD1 ASP A 503 −24.178 18.964 −34.879 1.00 82.05 O ATOM 775 OD2 ASP A 503 −24.938 17.836 −33.134 1.00 78.88 O ATOM 776 N LYS A 504 −25.761 23.314 −33.131 1.00 47.11 N ATOM 777 CA LYS A 504 −26.582 24.430 −33.574 1.00 41.50 C ATOM 778 C LYS A 504 −25.726 25.605 −34.073 1.00 34.69 C ATOM 779 O LYS A 504 −25.974 26.154 −35.145 1.00 39.09 O ATOM 780 CB LYS A 504 −27.517 24.849 −32.444 1.00 51.11 C ATOM 781 CG LYS A 504 −28.532 23.758 −32.138 1.00 59.48 C ATOM 782 CD LYS A 504 −29.400 23.530 −33.385 1.00 59.78 C ATOM 783 CE LYS A 504 −29.979 22.121 −33.461 1.00 53.56 C ATOM 784 NZ LYS A 504 −31.204 22.145 −34.326 1.00 58.33 N ATOM 785 N ILE A 505 −24.704 25.946 −33.296 1.00 38.17 N ATOM 786 CA ILE A 505 −23.808 27.068 −33.598 1.00 43.13 C ATOM 787 C ILE A 505 −22.992 26.848 −34.885 1.00 43.49 C ATOM 788 O ILE A 505 −22.812 27.768 −35.674 1.00 42.56 O ATOM 789 CB ILE A 505 −22.884 27.334 −32.365 1.00 44.16 C ATOM 790 CG1 ILE A 505 −23.693 27.977 −31.243 1.00 45.64 C ATOM 791 CG2 ILE A 505 −21.682 28.229 −32.695 1.00 43.62 C ATOM 792 CD1 ILE A 505 −22.893 28.175 −29.971 1.00 49.46 C ATOM 793 N LEU A 506 −22.503 25.632 −35.102 1.00 43.11 N ATOM 794 CA LEU A 506 −21.689 25.362 −36.291 1.00 47.49 C ATOM 795 C LEU A 506 −22.502 25.392 −37.579 1.00 49.85 C ATOM 796 O LEU A 506 −21.947 25.584 −38.672 1.00 43.51 O ATOM 797 CB LEU A 506 −20.980 24.019 −36.171 1.00 40.84 C ATOM 798 CG LEU A 506 −19.883 23.953 −35.108 1.00 43.79 C ATOM 799 CD1 LEU A 506 −19.263 22.559 −35.119 1.00 39.75 C ATOM 800 CD2 LEU A 506 −18.840 25.035 −35.365 1.00 43.93 C ATOM 801 N ARG A 507 −23.812 25.186 −37.459 1.00 42.71 N ATOM 802 CA ARG A 507 −24.686 25.238 −38.628 1.00 50.81 C ATOM 803 C ARG A 507 −25.262 26.625 −38.883 1.00 60.25 C ATOM 804 O ARG A 507 −26.035 26.803 −39.820 1.00 57.38 O ATOM 805 CB ARG A 507 −25.827 24.223 −38.508 1.00 51.12 C ATOM 806 CG ARG A 507 −25.358 22.796 −38.568 1.00 57.10 C ATOM 807 CD ARG A 507 −26.394 21.843 −38.018 1.00 69.33 C ATOM 808 NE ARG A 507 −25.837 20.504 −37.861 1.00 74.26 N ATOM 809 CZ ARG A 507 −25.738 19.634 −38.860 1.00 63.10 C ATOM 810 NH1 ARG A 507 −25.217 18.427 −38.658 1.00 51.88 N ATOM 811 NH2 ARG A 507 −26.159 19.975 −40.070 1.00 74.46 N ATOM 812 N GLN A 508 −24.896 27.605 −38.060 1.00 50.01 N ATOM 813 CA GLN A 508 −25.326 28.997 −38.307 1.00 47.42 C ATOM 814 C GLN A 508 −24.298 29.794 −39.097 1.00 54.12 C ATOM 815 O GLN A 508 −23.222 30.085 −38.580 1.00 56.49 O ATOM 816 CB GLN A 508 −25.566 29.721 −36.980 1.00 52.02 C ATOM 817 CG GLN A 508 −26.776 29.255 −36.211 1.00 60.94 C ATOM 818 CD GLN A 508 −27.054 30.135 −35.011 1.00 74.19 C ATOM 819 OE1 GLN A 508 −26.615 31.283 −34.957 1.00 81.70 O ATOM 820 NE2 GLN A 508 −27.784 29.603 −34.042 1.00 80.80 N ATOM 821 N LYS A 509 −24.630 30.201 −40.320 1.00 47.51 N ATOM 822 CA LYS A 509 −23.649 30.894 −41.153 1.00 60.66 C ATOM 823 C LYS A 509 −23.365 32.312 −40.684 1.00 61.81 C ATOM 824 O LYS A 509 −22.298 32.863 −40.966 1.00 53.39 O ATOM 825 CB LYS A 509 −24.059 30.903 −42.628 1.00 71.75 C ATOM 826 CG LYS A 509 −23.565 29.698 −43.409 1.00 87.43 C ATOM 827 CD LYS A 509 −24.376 28.458 −43.078 1.00 96.37 C ATOM 828 CE LYS A 509 −23.737 27.214 −43.657 1.00 96.42 C ATOM 829 NZ LYS A 509 −23.375 27.413 −45.079 1.00 98.30 N ATOM 830 N PHE A 510 −24.303 32.902 −39.952 1.00 51.35 N ATOM 831 CA PHE A 510 −24.177 34.324 −39.625 1.00 51.65 C ATOM 832 C PHE A 510 −23.748 34.564 −38.179 1.00 61.44 C ATOM 833 O PHE A 510 −23.906 35.648 −37.625 1.00 64.41 O ATOM 834 CB PHE A 510 −25.456 35.059 −40.005 1.00 47.78 C ATOM 835 CG PHE A 510 −25.655 35.128 −41.492 1.00 50.13 C ATOM 836 CD2 PHE A 510 −26.369 34.141 −42.160 1.00 53.82 C ATOM 837 CD1 PHE A 510 −25.070 36.139 −42.228 1.00 49.66 C ATOM 838 CE2 PHE A 510 −26.526 34.192 −43.536 1.00 53.67 C ATOM 839 CE1 PHE A 510 −25.235 36.201 −43.627 1.00 52.20 C ATOM 840 CZ PHE A 510 −25.959 35.222 −44.269 1.00 58.34 C ATOM 841 N PHE A 511 −23.144 33.541 −37.602 1.00 48.60 N ATOM 842 CA PHE A 511 −22.689 33.575 −36.218 1.00 46.62 C ATOM 843 C PHE A 511 −21.472 34.506 −36.112 1.00 42.18 C ATOM 844 O PHE A 511 −20.626 34.534 −37.022 1.00 54.94 O ATOM 845 CB PHE A 511 −22.340 32.149 −35.803 1.00 48.69 C ATOM 846 CG PHE A 511 −22.078 31.981 −34.342 1.00 47.80 C ATOM 847 CD1 PHE A 511 −23.124 31.939 −33.440 1.00 52.34 C ATOM 848 CD2 PHE A 511 −20.777 31.835 −33.873 1.00 57.48 C ATOM 849 CE1 PHE A 511 −22.881 31.769 −32.088 1.00 52.74 C ATOM 850 CE2 PHE A 511 −20.526 31.668 −32.529 1.00 51.55 C ATOM 851 CZ PHE A 511 −21.582 31.635 −31.631 1.00 48.56 C ATOM 852 N SER A 512 −21.388 35.275 −35.025 1.00 53.47 N ATOM 853 CA SER A 512 −20.327 36.280 −34.853 1.00 47.54 C ATOM 854 C SER A 512 −19.599 36.114 −33.525 1.00 49.01 C ATOM 855 O SER A 512 −20.075 35.421 −32.647 1.00 42.40 O ATOM 856 CB SER A 512 −20.917 37.694 −34.903 1.00 52.74 C ATOM 857 OG SER A 512 −21.831 37.891 −33.826 1.00 56.71 O ATOM 858 N GLU A 513 −18.450 36.773 −33.375 1.00 46.85 N ATOM 859 CA GLU A 513 −17.726 36.781 −32.105 1.00 49.81 C ATOM 860 C GLU A 513 −18.583 37.290 −30.948 1.00 52.64 C ATOM 861 O GLU A 513 −18.469 36.813 −29.808 1.00 43.22 O ATOM 862 CB GLU A 513 −16.467 37.653 −32.207 1.00 52.85 C ATOM 863 CG GLU A 513 −15.359 37.063 −33.046 1.00 61.32 C ATOM 864 CD GLU A 513 −14.037 37.772 −32.827 1.00 63.66 C ATOM 865 OE1 GLU A 513 −13.749 38.182 −31.673 1.00 55.10 O ATOM 866 OE2 GLU A 513 −13.284 37.923 −33.811 1.00 51.31 O ATOM 867 N ARG A 514 −19.416 38.280 −31.241 1.00 45.58 N ATOM 868 CA ARG A 514 −20.311 38.849 −30.245 1.00 51.99 C ATOM 869 C ARG A 514 −21.194 37.764 −29.651 1.00 50.00 C ATOM 870 O ARG A 514 −21.372 37.665 −28.433 1.00 45.21 O ATOM 871 CB ARG A 514 −21.187 39.912 −30.897 1.00 54.99 C ATOM 872 CG ARG A 514 −21.976 40.753 −29.926 1.00 79.96 C ATOM 873 CD ARG A 514 −21.246 42.048 −29.636 1.00 91.72 C ATOM 874 NE ARG A 514 −21.080 42.864 −30.835 1.00 98.18 N ATOM 875 CZ ARG A 514 −21.848 43.905 −31.144 1.00 102.81 C ATOM 876 NH1 ARG A 514 −22.838 44.265 −30.338 1.00 97.13 N ATOM 877 NH2 ARG A 514 −21.623 44.589 −32.256 1.00 108.98 N ATOM 878 N GLU A 515 −21.754 36.942 −30.522 1.00 46.44 N ATOM 879 CA GLU A 515 −22.570 35.831 −30.064 1.00 45.26 C ATOM 880 C GLU A 515 −21.766 34.723 −29.390 1.00 47.88 C ATOM 881 O GLU A 515 −22.263 34.075 −28.477 1.00 41.64 O ATOM 882 CB GLU A 515 −23.414 35.275 −31.216 1.00 53.07 C ATOM 883 CG GLU A 515 −24.664 36.114 −31.465 1.00 67.46 C ATOM 884 CD GLU A 515 −25.237 36.706 −30.166 1.00 93.12 C ATOM 885 OE1 GLU A 515 −25.936 35.982 −29.419 1.00 97.39 O ATOM 886 OE2 GLU A 515 −24.991 37.903 −29.890 1.00 99.77 O ATOM 887 N ALA A 516 −20.534 34.496 −29.844 1.00 46.76 N ATOM 888 CA ALA A 516 −19.698 33.469 −29.229 1.00 39.69 C ATOM 889 C ALA A 516 −19.356 33.881 −27.797 1.00 42.62 C ATOM 890 O ALA A 516 −19.323 33.044 −26.898 1.00 36.58 O ATOM 891 CB ALA A 516 −18.418 33.240 −30.036 1.00 39.68 C ATOM 892 N SER A 517 −19.110 35.175 −27.609 1.00 39.35 N ATOM 893 CA SER A 517 −18.799 35.730 −26.303 1.00 40.22 C ATOM 894 C SER A 517 −19.980 35.609 −25.355 1.00 43.04 C ATOM 895 O SER A 517 −19.807 35.200 −24.210 1.00 40.22 O ATOM 896 CB SER A 517 −18.358 37.193 −26.433 1.00 47.11 C ATOM 897 OG SER A 517 −17.956 37.713 −25.176 1.00 49.04 O ATOM 898 N ALA A 518 −21.180 35.949 −25.826 1.00 42.31 N ATOM 899 CA ALA A 518 −22.369 35.784 −24.987 1.00 44.87 C ATOM 900 C ALA A 518 −22.528 34.328 −24.528 1.00 45.63 C ATOM 901 O ALA A 518 −22.824 34.061 −23.356 1.00 43.17 O ATOM 902 CB ALA A 518 −23.640 36.280 −25.705 1.00 46.44 C ATOM 903 N VAL A 519 −22.319 33.388 −25.445 1.00 38.24 N ATOM 904 CA VAL A 519 −22.393 31.968 −25.102 1.00 40.27 C ATOM 905 C VAL A 519 −21.317 31.520 −24.114 1.00 42.86 C ATOM 906 O VAL A 519 −21.618 30.857 −23.108 1.00 41.53 O ATOM 907 CB VAL A 519 −22.326 31.088 −26.366 1.00 38.82 C ATOM 908 CG1 VAL A 519 −22.028 29.632 −25.993 1.00 41.43 C ATOM 909 CG2 VAL A 519 −23.624 31.217 −27.173 1.00 46.53 C ATOM 910 N LEU A 520 −20.059 31.869 −24.379 1.00 37.30 N ATOM 911 CA LEU A 520 −19.003 31.516 −23.438 1.00 44.12 C ATOM 912 C LEU A 520 −19.248 32.141 −22.058 1.00 39.46 C ATOM 913 O LEU A 520 −18.998 31.507 −21.034 1.00 36.62 O ATOM 914 CB LEU A 520 −17.614 31.904 −23.975 1.00 35.95 C ATOM 915 CG LEU A 520 −16.438 31.436 −23.108 1.00 53.96 C ATOM 916 CD1 LEU A 520 −16.456 29.921 −22.929 1.00 42.20 C ATOM 917 CD2 LEU A 520 −15.094 31.892 −23.687 1.00 58.16 C ATOM 918 N PHE A 521 −19.736 33.375 −22.031 1.00 38.19 N ATOM 919 CA PHE A 521 −19.982 34.057 −20.759 1.00 41.94 C ATOM 920 C PHE A 521 −20.979 33.271 −19.917 1.00 50.33 C ATOM 921 O PHE A 521 −20.730 33.001 −18.743 1.00 41.44 O ATOM 922 CB PHE A 521 −20.527 35.477 −20.988 1.00 39.48 C ATOM 923 CG PHE A 521 −21.111 36.112 −19.743 1.00 50.05 C ATOM 924 CD1 PHE A 521 −20.281 36.640 −18.757 1.00 48.93 C ATOM 925 CD2 PHE A 521 −22.489 36.179 −19.559 1.00 50.85 C ATOM 926 CE1 PHE A 521 −20.818 37.225 −17.604 1.00 56.13 C ATOM 927 CE2 PHE A 521 −23.029 36.755 −18.415 1.00 53.14 C ATOM 928 CZ PHE A 521 −22.191 37.284 −17.436 1.00 58.43 C ATOM 929 N THR A 522 −22.115 32.927 −20.525 1.00 44.17 N ATOM 930 CA THR A 522 −23.164 32.179 −19.835 1.00 39.19 C ATOM 931 C THR A 522 −22.647 30.857 −19.280 1.00 43.18 C ATOM 932 O THR A 522 −22.882 30.496 −18.109 1.00 38.43 O ATOM 933 CB THR A 522 −24.331 31.915 −20.789 1.00 46.53 C ATOM 934 OG1 THR A 522 −24.933 33.169 −21.128 1.00 43.18 O ATOM 935 CG2 THR A 522 −25.369 31.010 −20.137 1.00 43.99 C ATOM 936 N ILE A 523 −21.906 30.143 −20.109 1.00 35.82 N ATOM 937 CA ILE A 523 −21.339 28.865 −19.681 1.00 38.56 C ATOM 938 C ILE A 523 −20.274 29.036 −18.617 1.00 44.89 C ATOM 939 O ILE A 523 −20.266 28.308 −17.626 1.00 38.18 O ATOM 940 CB ILE A 523 −20.754 28.091 −20.878 1.00 39.30 C ATOM 941 CG1 ILE A 523 −21.878 27.752 −21.878 1.00 40.35 C ATOM 942 CG2 ILE A 523 −20.008 26.842 −20.394 1.00 36.07 C ATOM 943 CD1 ILE A 523 −21.353 27.295 −23.291 1.00 40.97 C ATOM 944 N THR A 524 −19.371 29.991 −18.806 1.00 39.97 N ATOM 945 CA THR A 524 −18.260 30.128 −17.867 1.00 40.42 C ATOM 946 C THR A 524 −18.751 30.649 −16.510 1.00 44.05 C ATOM 947 O THR A 524 −18.200 30.309 −15.462 1.00 43.70 O ATOM 948 CB THR A 524 −17.170 31.053 −18.419 1.00 41.81 C ATOM 949 OG1 THR A 524 −16.774 30.579 −19.713 1.00 44.20 O ATOM 950 CG2 THR A 524 −15.951 31.081 −17.481 1.00 44.47 C ATOM 951 N LYS A 525 −19.791 31.472 −16.531 1.00 36.44 N ATOM 952 CA LYS A 525 −20.404 31.962 −15.286 1.00 46.98 C ATOM 953 C LYS A 525 −20.898 30.800 −14.437 1.00 45.64 C ATOM 954 O LYS A 525 −20.820 30.812 −13.194 1.00 45.88 O ATOM 955 CB LYS A 525 −21.600 32.843 −15.624 1.00 48.44 C ATOM 956 CG LYS A 525 −21.391 34.295 −15.366 1.00 60.84 C ATOM 957 CD LYS A 525 −21.428 34.553 −13.891 1.00 68.50 C ATOM 958 CE LYS A 525 −20.968 35.953 −13.572 1.00 83.23 C ATOM 959 NZ LYS A 525 −21.031 36.208 −12.109 1.00 85.81 N ATOM 960 N THR A 526 −21.427 29.801 −15.129 1.00 44.01 N ATOM 961 CA THR A 526 −21.996 28.628 −14.492 1.00 43.39 C ATOM 962 C THR A 526 −20.889 27.774 −13.911 1.00 44.97 C ATOM 963 O THR A 526 −21.013 27.229 −12.807 1.00 45.05 O ATOM 964 CB THR A 526 −22.800 27.814 −15.519 1.00 49.47 C ATOM 965 OG1 THR A 526 −23.815 28.654 −16.092 1.00 42.80 O ATOM 966 CG2 THR A 526 −23.449 26.615 −14.860 1.00 42.52 C ATOM 967 N VAL A 527 −19.804 27.655 −14.663 1.00 37.84 N ATOM 968 CA VAL A 527 −18.632 26.882 −14.222 1.00 36.68 C ATOM 969 C VAL A 527 −17.952 27.579 −13.048 1.00 47.43 C ATOM 970 O VAL A 527 −17.495 26.930 −12.093 1.00 47.77 O ATOM 971 CB VAL A 527 −17.657 26.652 −15.408 1.00 35.64 C ATOM 972 CG1 VAL A 527 −16.314 26.071 −14.938 1.00 37.07 C ATOM 973 CG2 VAL A 527 −18.297 25.754 −16.478 1.00 37.19 C ATOM 974 N GLU A 528 −17.910 28.908 −13.088 1.00 43.21 N ATOM 975 CA GLU A 528 −17.279 29.641 −11.988 1.00 50.31 C ATOM 976 C GLU A 528 −18.038 29.406 −10.692 1.00 51.84 C ATOM 977 O GLU A 528 −17.430 29.253 −9.633 1.00 50.06 O ATOM 978 CB GLU A 528 −17.203 31.148 −12.270 1.00 47.88 C ATOM 979 CG GLU A 528 −16.447 31.917 −11.166 1.00 57.92 C ATOM 980 CD GLU A 528 −16.781 33.397 −11.141 1.00 67.13 C ATOM 981 OE1 GLU A 528 −15.849 34.213 −10.958 1.00 67.89 O ATOM 982 OE2 GLU A 528 −17.975 33.747 −11.305 1.00 61.15 O ATOM 983 N TYR A 529 −19.368 29.395 −10.786 1.00 46.83 N ATOM 984 CA TYR A 529 −20.220 29.162 −9.619 1.00 53.15 C ATOM 985 C TYR A 529 −19.960 27.780 −9.028 1.00 55.04 C ATOM 986 O TYR A 529 −19.759 27.634 −7.821 1.00 55.31 O ATOM 987 CB TYR A 529 −21.694 29.292 −10.001 1.00 45.52 C ATOM 988 CG TYR A 529 −22.635 28.812 −8.921 1.00 53.63 C ATOM 989 CD1 TYR A 529 −22.818 29.550 −7.750 1.00 59.08 C ATOM 990 CD2 TYR A 529 −23.333 27.621 −9.057 1.00 50.42 C ATOM 991 CE1 TYR A 529 −23.678 29.119 −6.750 1.00 57.32 C ATOM 992 CE2 TYR A 529 −24.203 27.181 −8.054 1.00 56.34 C ATOM 993 CZ TYR A 529 −24.368 27.936 −6.905 1.00 56.15 C ATOM 994 OH TYR A 529 −25.220 27.519 −5.908 1.00 55.99 O ATOM 995 N LEU A 530 −19.965 26.773 −9.896 1.00 48.63 N ATOM 996 CA LEU A 530 −19.684 25.390 −9.507 1.00 52.33 C ATOM 997 C LEU A 530 −18.319 25.216 −8.830 1.00 54.36 C ATOM 998 O LEU A 530 −18.209 24.638 −7.736 1.00 51.02 O ATOM 999 CB LEU A 530 −19.803 24.489 −10.748 1.00 45.87 C ATOM 1000 CG LEU A 530 −21.254 24.229 −11.162 1.00 51.27 C ATOM 1001 CD1 LEU A 530 −21.335 23.569 −12.535 1.00 45.59 C ATOM 1002 CD2 LEU A 530 −21.964 23.381 −10.123 1.00 50.70 C ATOM 1003 N HIS A 531 −17.276 25.740 −9.461 1.00 46.41 N ATOM 1004 CA HIS A 531 −15.926 25.615 −8.902 1.00 48.23 C ATOM 1005 C HIS A 531 −15.822 26.262 −7.528 1.00 54.40 C ATOM 1006 O HIS A 531 −15.128 25.757 −6.649 1.00 54.69 O ATOM 1007 CB HIS A 531 −14.883 26.220 −9.835 1.00 48.87 C ATOM 1008 CG HIS A 531 −14.622 25.400 −11.061 1.00 45.72 C ATOM 1009 ND1 HIS A 531 −13.768 25.810 −12.065 1.00 49.30 N ATOM 1010 CD2 HIS A 531 −15.107 24.194 −11.450 1.00 40.60 C ATOM 1011 CE1 HIS A 531 −13.726 24.888 −13.011 1.00 49.55 C ATOM 1012 NE2 HIS A 531 −14.531 23.899 −12.665 1.00 43.23 N ATOM 1013 N ALA A 532 −16.526 27.376 −7.353 1.00 53.41 N ATOM 1014 CA ALA A 532 −16.520 28.102 −6.087 1.00 60.53 C ATOM 1015 C ALA A 532 −17.285 27.357 −5.001 1.00 56.21 C ATOM 1016 O ALA A 532 −17.040 27.553 −3.800 1.00 58.08 O ATOM 1017 CB ALA A 532 −17.113 29.488 −6.288 1.00 63.00 C ATOM 1018 N GLN A 533 −18.235 26.524 −5.415 1.00 54.01 N ATOM 1019 CA GLN A 533 −19.009 25.730 −4.465 1.00 58.16 C ATOM 1020 C GLN A 533 −18.304 24.402 −4.199 1.00 61.04 C ATOM 1021 O GLN A 533 −18.774 23.567 −3.429 1.00 57.30 O ATOM 1022 CB GLN A 533 −20.418 25.494 −4.996 1.00 61.67 C ATOM 1023 CG GLN A 533 −21.219 26.778 −5.176 1.00 52.37 C ATOM 1024 CD GLN A 533 −21.390 27.540 −3.882 1.00 69.76 C ATOM 1025 OE1 GLN A 533 −21.541 26.946 −2.814 1.00 69.15 O ATOM 1026 NE2 GLN A 533 −21.359 28.864 −3.968 1.00 81.08 N ATOM 1027 N GLY A 534 −17.159 24.227 −4.845 1.00 55.01 N ATOM 1028 CA GLY A 534 −16.353 23.033 −4.674 1.00 61.08 C ATOM 1029 C GLY A 534 −16.694 21.897 −5.623 1.00 58.88 C ATOM 1030 O GLY A 534 −16.373 20.742 −5.343 1.00 58.80 O ATOM 1031 N VAL A 535 −17.338 22.210 −6.748 1.00 50.49 N ATOM 1032 CA VAL A 535 −17.756 21.176 −7.685 1.00 43.48 C ATOM 1033 C VAL A 535 −16.954 21.277 −8.979 1.00 46.58 C ATOM 1034 O VAL A 535 −16.913 22.341 −9.592 1.00 46.53 O ATOM 1035 CB VAL A 535 −19.266 21.298 −8.028 1.00 43.49 C ATOM 1036 CG1 VAL A 535 −19.664 20.297 −9.103 1.00 44.34 C ATOM 1037 CG2 VAL A 535 −20.102 21.111 −6.796 1.00 50.39 C ATOM 1038 N VAL A 536 −16.291 20.183 −9.367 1.00 52.70 N ATOM 1039 CA VAL A 536 −15.681 20.067 −10.699 1.00 48.52 C ATOM 1040 C VAL A 536 −16.511 19.117 −11.568 1.00 47.75 C ATOM 1041 O VAL A 536 −16.985 18.086 −11.092 1.00 46.09 O ATOM 1042 CB VAL A 536 −14.223 19.569 −10.636 1.00 44.76 C ATOM 1043 CG1 VAL A 536 −13.325 20.670 −10.148 1.00 47.35 C ATOM 1044 CG2 VAL A 536 −14.100 18.343 −9.740 1.00 46.95 C ATOM 1045 N HIS A 537 −16.690 19.473 −12.836 1.00 44.14 N ATOM 1046 CA HIS A 537 −17.547 18.714 −13.744 1.00 47.47 C ATOM 1047 C HIS A 537 −16.869 17.433 −14.242 1.00 50.85 C ATOM 1048 O HIS A 537 −17.455 16.355 −14.160 1.00 46.13 O ATOM 1049 CB HIS A 537 −18.002 19.576 −14.932 1.00 45.24 C ATOM 1050 CG HIS A 537 −19.057 18.924 −15.775 1.00 43.14 C ATOM 1051 ND1 HIS A 537 −18.777 17.902 −16.658 1.00 37.01 N ATOM 1052 CD2 HIS A 537 −20.396 19.134 −15.856 1.00 40.94 C ATOM 1053 CE1 HIS A 537 −19.893 17.518 −17.251 1.00 44.97 C ATOM 1054 NE2 HIS A 537 −20.889 18.248 −16.781 1.00 42.17 N ATOM 1055 N ARG A 538 −15.649 17.560 −14.769 1.00 45.32 N ATOM 1056 CA ARG A 538 −14.817 16.411 −15.149 1.00 45.72 C ATOM 1057 C ARG A 538 −15.207 15.728 −16.479 1.00 39.75 C ATOM 1058 O ARG A 538 −14.466 14.883 −16.991 1.00 48.52 O ATOM 1059 CB ARG A 538 −14.695 15.387 −14.006 1.00 50.00 C ATOM 1060 CG ARG A 538 −14.168 15.975 −12.687 1.00 51.59 C ATOM 1061 CD ARG A 538 −13.922 14.914 −11.603 1.00 53.43 C ATOM 1062 NE ARG A 538 −12.834 14.004 −11.964 1.00 72.80 N ATOM 1063 CZ ARG A 538 −13.016 12.750 −12.369 1.00 74.44 C ATOM 1064 NH1 ARG A 538 −14.247 12.259 −12.461 1.00 66.10 N ATOM 1065 NH2 ARG A 538 −11.971 11.987 −12.678 1.00 69.84 N ATOM 1066 N ASP A 539 −16.353 16.085 −17.040 1.00 45.64 N ATOM 1067 CA ASP A 539 −16.720 15.563 −18.359 1.00 45.45 C ATOM 1068 C ASP A 539 −17.336 16.668 −19.216 1.00 49.98 C ATOM 1069 O ASP A 539 −18.368 16.472 −19.861 1.00 40.78 O ATOM 1070 CB ASP A 539 −17.708 14.393 −18.214 1.00 65.97 C ATOM 1071 CG ASP A 539 −17.884 13.602 −19.509 1.00 64.04 C ATOM 1072 OD1 ASP A 539 −16.911 13.508 −20.286 1.00 57.98 O ATOM 1073 OD2 ASP A 539 −18.994 13.073 −19.750 1.00 66.09 O ATOM 1074 N LEU A 540 −16.704 17.834 −19.221 1.00 39.27 N ATOM 1075 CA LEU A 540 −17.328 19.027 −19.794 1.00 34.55 C ATOM 1076 C LEU A 540 −17.090 19.156 −21.296 1.00 43.81 C ATOM 1077 O LEU A 540 −16.753 20.222 −21.808 1.00 43.35 O ATOM 1078 CB LEU A 540 −16.889 20.278 −19.023 1.00 41.00 C ATOM 1079 CG LEU A 540 −17.625 21.607 −19.167 1.00 41.07 C ATOM 1080 CD1 LEU A 540 −19.155 21.441 −18.934 1.00 42.09 C ATOM 1081 CD2 LEU A 540 −17.035 22.600 −18.175 1.00 39.69 C ATOM 1082 N LYS A 541 −17.296 18.060 −22.012 1.00 38.50 N ATOM 1083 CA LYS A 541 −17.196 18.101 −23.469 1.00 41.16 C ATOM 1084 C LYS A 541 −18.387 18.803 −24.091 1.00 44.52 C ATOM 1085 O LYS A 541 −19.461 18.880 −23.476 1.00 41.51 O ATOM 1086 CB LYS A 541 −17.010 16.695 −24.045 1.00 47.70 C ATOM 1087 CG LYS A 541 −18.039 15.670 −23.628 1.00 48.98 C ATOM 1088 CD LYS A 541 −17.495 14.262 −23.877 1.00 46.93 C ATOM 1089 CE LYS A 541 −18.591 13.215 −23.770 1.00 55.15 C ATOM 1090 NZ LYS A 541 −18.042 11.850 −24.011 1.00 52.19 N ATOM 1091 N PRO A 542 −18.198 19.351 −25.306 1.00 39.77 N ATOM 1092 CA PRO A 542 −19.266 20.060 −26.021 1.00 38.27 C ATOM 1093 C PRO A 542 −20.588 19.293 −26.067 1.00 39.32 C ATOM 1094 O PRO A 542 −21.661 19.902 −25.995 1.00 40.92 O ATOM 1095 CB PRO A 542 −18.689 20.221 −27.437 1.00 46.04 C ATOM 1096 CG PRO A 542 −17.213 20.401 −27.194 1.00 45.41 C ATOM 1097 CD PRO A 542 −16.880 19.550 −25.954 1.00 36.60 C ATOM 1098 N SER A 543 −20.540 17.972 −26.172 1.00 35.93 N ATOM 1099 CA SER A 543 −21.807 17.254 −26.310 1.00 41.15 C ATOM 1100 C SER A 543 −22.586 17.228 −24.986 1.00 38.51 C ATOM 1101 O SER A 543 −23.728 16.769 −24.946 1.00 45.59 O ATOM 1102 CB SER A 543 −21.580 15.843 −26.844 1.00 44.01 C ATOM 1103 OG SER A 543 −20.717 15.125 −25.976 1.00 47.33 O ATOM 1104 N ASN A 544 −21.979 17.712 −23.903 1.00 35.63 N ATOM 1105 CA ASN A 544 −22.703 17.782 −22.630 1.00 38.84 C ATOM 1106 C ASN A 544 −23.248 19.181 −22.353 1.00 39.85 C ATOM 1107 O ASN A 544 −23.682 19.482 −21.243 1.00 42.61 O ATOM 1108 CB ASN A 544 −21.842 17.275 −21.474 1.00 37.11 C ATOM 1109 CG ASN A 544 −21.804 15.766 −21.437 1.00 41.09 C ATOM 1110 OD1 ASN A 544 −22.745 15.121 −21.914 1.00 41.04 O ATOM 1111 ND2 ASN A 544 −20.733 15.195 −20.901 1.00 38.70 N ATOM 1112 N ILE A 545 −23.196 20.037 −23.367 1.00 34.27 N ATOM 1113 CA ILE A 545 −23.695 21.400 −23.228 1.00 36.15 C ATOM 1114 C ILE A 545 −24.764 21.569 −24.274 1.00 47.98 C ATOM 1115 O ILE A 545 −24.480 21.523 −25.468 1.00 38.44 O ATOM 1116 CB ILE A 545 −22.576 22.435 −23.420 1.00 39.43 C ATOM 1117 CG1 ILE A 545 −21.481 22.193 −22.378 1.00 43.27 C ATOM 1118 CG2 ILE A 545 −23.142 23.866 −23.318 1.00 36.12 C ATOM 1119 CD1 ILE A 545 −20.379 23.225 −22.389 1.00 41.93 C ATOM 1120 N LEU A 546 −26.005 21.726 −23.828 1.00 34.70 N ATOM 1121 CA LEU A 546 −27.139 21.673 −24.744 1.00 34.93 C ATOM 1122 C LEU A 546 −28.020 22.908 −24.623 1.00 38.13 C ATOM 1123 O LEU A 546 −27.867 23.710 −23.707 1.00 37.41 O ATOM 1124 CB LEU A 546 −28.017 20.442 −24.461 1.00 41.33 C ATOM 1125 CG LEU A 546 −27.575 18.972 −24.572 1.00 56.63 C ATOM 1126 CD1 LEU A 546 −28.513 18.214 −25.501 1.00 58.32 C ATOM 1127 CD2 LEU A 546 −26.171 18.781 −25.042 1.00 57.44 C ATOM 1128 N TYR A 547 −28.957 23.028 −25.553 1.00 37.22 N ATOM 1129 CA TYR A 547 −29.983 24.052 −25.526 1.00 37.77 C ATOM 1130 C TYR A 547 −31.290 23.384 −25.122 1.00 45.37 C ATOM 1131 O TYR A 547 −31.650 22.353 −25.685 1.00 43.34 O ATOM 1132 CB TYR A 547 −30.172 24.629 −26.931 1.00 38.98 C ATOM 1133 CG TYR A 547 −29.188 25.701 −27.334 1.00 47.12 C ATOM 1134 CD1 TYR A 547 −29.118 26.912 −26.646 1.00 42.91 C ATOM 1135 CD2 TYR A 547 −28.356 25.521 −28.430 1.00 45.73 C ATOM 1136 CE1 TYR A 547 −28.234 27.918 −27.042 1.00 45.84 C ATOM 1137 CE2 TYR A 547 −27.466 26.510 −28.828 1.00 47.52 C ATOM 1138 CZ TYR A 547 −27.411 27.706 −28.137 1.00 51.98 C ATOM 1139 OH TYR A 547 −26.518 28.675 −28.543 1.00 43.91 O ATOM 1140 N VAL A 548 −32.003 23.954 −24.152 1.00 42.14 N ATOM 1141 CA VAL A 548 −33.238 23.331 −23.685 1.00 42.26 C ATOM 1142 C VAL A 548 −34.370 23.520 −24.702 1.00 42.94 C ATOM 1143 O VAL A 548 −35.285 22.681 −24.799 1.00 44.13 O ATOM 1144 CB VAL A 548 −33.675 23.846 −22.266 1.00 49.20 C ATOM 1145 CG1 VAL A 548 −34.041 25.320 −22.302 1.00 45.56 C ATOM 1146 CG2 VAL A 548 −34.851 23.030 −21.739 1.00 44.53 C ATOM 1147 N ASP A 549 −34.304 24.611 −25.465 1.00 46.19 N ATOM 1148 CA ASP A 549 −35.294 24.865 −26.514 1.00 47.80 C ATOM 1149 C ASP A 549 −34.630 25.378 −27.792 1.00 50.65 C ATOM 1150 O ASP A 549 −33.401 25.402 −27.888 1.00 45.39 O ATOM 1151 CB ASP A 549 −36.377 25.833 −26.018 1.00 52.66 C ATOM 1152 CG ASP A 549 −35.798 27.112 −25.442 1.00 58.17 C ATOM 1153 OD2 ASP A 549 −36.241 27.532 −24.357 1.00 68.78 O ATOM 1154 OD1 ASP A 549 −34.898 27.703 −26.072 1.00 51.79 O ATOM 1155 N GLU A 550 −35.435 25.797 −28.765 1.00 49.97 N ATOM 1156 CA GLU A 550 −34.894 26.260 −30.040 1.00 64.81 C ATOM 1157 C GLU A 550 −34.825 27.779 −30.159 1.00 62.88 C ATOM 1158 O GLU A 550 −34.710 28.308 −31.259 1.00 67.05 O ATOM 1159 CB GLU A 550 −35.718 25.706 −31.206 1.00 70.31 C ATOM 1160 CG GLU A 550 −35.640 24.197 −31.394 1.00 85.28 C ATOM 1161 CD GLU A 550 −36.508 23.710 −32.548 1.00 94.03 C ATOM 1162 OE1 GLU A 550 −37.345 24.493 −33.051 1.00 93.69 O ATOM 1163 OE2 GLU A 550 −36.353 22.539 −32.954 1.00 99.55 O ATOM 1164 N SER A 551 −34.892 28.484 −29.036 1.00 53.77 N ATOM 1165 CA SER A 551 −34.913 29.948 −29.058 1.00 57.03 C ATOM 1166 C SER A 551 −33.571 30.555 −29.474 1.00 55.17 C ATOM 1167 O SER A 551 −33.498 31.717 −29.871 1.00 64.24 O ATOM 1168 CB SER A 551 −35.281 30.476 −27.680 1.00 62.75 C ATOM 1169 OG SER A 551 −34.307 30.054 −26.733 1.00 57.19 O ATOM 1170 N GLY A 552 −32.507 29.769 −29.353 1.00 50.27 N ATOM 1171 CA GLY A 552 −31.168 30.225 −29.675 1.00 54.00 C ATOM 1172 C GLY A 552 −30.534 31.187 −28.683 1.00 65.76 C ATOM 1173 O GLY A 552 −29.424 31.678 −28.919 1.00 57.85 O ATOM 1174 N ASN A 553 −31.212 31.468 −27.571 1.00 49.89 N ATOM 1175 CA ASN A 553 −30.652 32.419 −26.612 1.00 58.58 C ATOM 1176 C ASN A 553 −29.808 31.787 −25.502 1.00 52.87 C ATOM 1177 O ASN A 553 −30.070 30.664 −25.067 1.00 47.25 O ATOM 1178 CB ASN A 553 −31.732 33.343 −26.042 1.00 77.46 C ATOM 1179 CG ASN A 553 −33.078 32.686 −25.972 1.00 92.84 C ATOM 1180 OD1 ASN A 553 −33.205 31.560 −25.492 1.00 103.27 O ATOM 1181 ND2 ASN A 553 −34.102 33.378 −26.468 1.00 88.37 N ATOM 1182 N PRO A 554 −28.772 32.511 −25.060 1.00 58.43 N ATOM 1183 CA PRO A 554 −27.857 32.010 −24.030 1.00 57.78 C ATOM 1184 C PRO A 554 −28.582 31.493 −22.782 1.00 54.27 C ATOM 1185 O PRO A 554 −28.130 30.517 −22.202 1.00 52.47 O ATOM 1186 CB PRO A 554 −26.998 33.232 −23.714 1.00 58.37 C ATOM 1187 CG PRO A 554 −26.972 33.995 −25.004 1.00 53.90 C ATOM 1188 CD PRO A 554 −28.354 33.829 −25.577 1.00 58.41 C ATOM 1189 N GLU A 555 −29.710 32.104 −22.412 1.00 48.66 N ATOM 1190 CA GLU A 555 −30.493 31.671 −21.243 1.00 52.53 C ATOM 1191 C GLU A 555 −31.014 30.227 −21.351 1.00 53.94 C ATOM 1192 O GLU A 555 −31.375 29.606 −20.353 1.00 54.14 O ATOM 1193 CB GLU A 555 −31.679 32.615 −21.012 1.00 57.21 C ATOM 1194 CG GLU A 555 −31.312 34.093 −20.812 1.00 83.20 C ATOM 1195 CD GLU A 555 −31.000 34.841 −22.111 1.00 92.07 C ATOM 1196 OE1 GLU A 555 −30.976 36.092 −22.080 1.00 102.94 O ATOM 1197 OE2 GLU A 555 −30.772 34.199 −23.162 1.00 76.11 O ATOM 1198 N SER A 556 −31.072 29.700 −22.566 1.00 48.17 N ATOM 1199 CA SER A 556 −31.601 28.355 −22.778 1.00 39.93 C ATOM 1200 C SER A 556 −30.486 27.302 −22.770 1.00 41.41 C ATOM 1201 O SER A 556 −30.743 26.121 −22.980 1.00 40.15 O ATOM 1202 CB SER A 556 −32.363 28.288 −24.103 1.00 49.56 C ATOM 1203 OG SER A 556 −31.436 28.348 −25.168 1.00 50.24 O ATOM 1204 N ILE A 557 −29.253 27.729 −22.523 1.00 32.46 N ATOM 1205 CA ILE A 557 −28.130 26.779 −22.422 1.00 30.87 C ATOM 1206 C ILE A 557 −28.198 25.971 −21.119 1.00 32.44 C ATOM 1207 O ILE A 557 −28.531 26.517 −20.059 1.00 40.14 O ATOM 1208 CB ILE A 557 −26.802 27.561 −22.452 1.00 37.79 C ATOM 1209 CG1 ILE A 557 −26.618 28.235 −23.826 1.00 47.87 C ATOM 1210 CG2 ILE A 557 −25.628 26.651 −22.107 1.00 34.88 C ATOM 1211 CD1 ILE A 557 −25.493 29.264 −23.841 1.00 49.44 C ATOM 1212 N ARG A 558 −27.880 24.675 −21.177 1.00 32.27 N ATOM 1213 CA ARG A 558 −27.791 23.872 −19.958 1.00 32.43 C ATOM 1214 C ARG A 558 −26.527 23.048 −20.005 1.00 33.83 C ATOM 1215 O ARG A 558 −26.253 22.398 −21.019 1.00 38.67 O ATOM 1216 CB ARG A 558 −28.970 22.909 −19.854 1.00 38.59 C ATOM 1217 CG ARG A 558 −30.329 23.603 −19.810 1.00 37.48 C ATOM 1218 CD ARG A 558 −30.551 24.318 −18.470 1.00 38.91 C ATOM 1219 NE ARG A 558 −31.939 24.812 −18.403 1.00 43.84 N ATOM 1220 CZ ARG A 558 −32.345 25.977 −18.893 1.00 49.79 C ATOM 1221 NH1 ARG A 558 −31.488 26.790 −19.496 1.00 46.05 N ATOM 1222 NH2 ARG A 558 −33.617 26.333 −18.783 1.00 48.40 N ATOM 1223 N ILE A 559 −25.768 23.100 −18.922 1.00 35.09 N ATOM 1224 CA ILE A 559 −24.711 22.125 −18.695 1.00 36.16 C ATOM 1225 C ILE A 559 −25.347 20.855 −18.128 1.00 44.08 C ATOM 1226 O ILE A 559 −26.093 20.905 −17.143 1.00 41.39 O ATOM 1227 CB ILE A 559 −23.662 22.666 −17.706 1.00 41.29 C ATOM 1228 CG1 ILE A 559 −23.055 23.966 −18.256 1.00 40.26 C ATOM 1229 CG2 ILE A 559 −22.578 21.612 −17.434 1.00 39.41 C ATOM 1230 CD1 ILE A 559 −21.866 24.481 −17.408 1.00 40.73 C ATOM 1231 N CYS A 560 −25.056 19.721 −18.760 1.00 40.80 N ATOM 1232 CA CYS A 560 −25.665 18.444 −18.404 1.00 40.65 C ATOM 1233 C CYS A 560 −24.626 17.387 −18.054 1.00 45.22 C ATOM 1234 O CYS A 560 −23.412 17.627 −18.130 1.00 45.70 O ATOM 1235 CB CYS A 560 −26.505 17.905 −19.567 1.00 39.51 C ATOM 1236 SG CYS A 560 −27.752 19.073 −20.235 1.00 46.36 S ATOM 1237 N ASP A 561 −25.135 16.211 −17.694 1.00 45.35 N ATOM 1238 CA ASP A 561 −24.333 15.038 −17.320 1.00 45.53 C ATOM 1239 C ASP A 561 −23.283 15.266 −16.236 1.00 49.18 C ATOM 1240 O ASP A 561 −22.086 15.444 −16.505 1.00 43.19 O ATOM 1241 CB ASP A 561 −23.704 14.367 −18.545 1.00 51.99 C ATOM 1242 CG ASP A 561 −23.315 12.912 −18.277 1.00 62.55 C ATOM 1243 OD1 ASP A 561 −23.353 12.476 −17.104 1.00 62.28 O ATOM 1244 OD2 ASP A 561 −22.963 12.201 −19.242 1.00 65.81 O ATOM 1245 N PHE A 562 −23.735 15.194 −14.997 1.00 40.57 N ATOM 1246 CA PHE A 562 −22.857 15.339 −13.853 1.00 44.10 C ATOM 1247 C PHE A 562 −22.455 13.975 −13.291 1.00 46.83 C ATOM 1248 O PHE A 562 −22.116 13.847 −12.114 1.00 46.88 O ATOM 1249 CB PHE A 562 −23.550 16.207 −12.797 1.00 43.23 C ATOM 1250 CG PHE A 562 −23.568 17.669 −13.154 1.00 42.71 C ATOM 1251 CD1 PHE A 562 −24.466 18.159 −14.100 1.00 44.38 C ATOM 1252 CD2 PHE A 562 −22.662 18.543 −12.575 1.00 47.62 C ATOM 1253 CE1 PHE A 562 −24.478 19.513 −14.445 1.00 41.33 C ATOM 1254 CE2 PHE A 562 −22.658 19.890 −12.905 1.00 44.19 C ATOM 1255 CZ PHE A 562 −23.570 20.381 −13.842 1.00 41.25 C ATOM 1256 N GLY A 563 −22.480 12.958 −14.146 1.00 47.72 N ATOM 1257 CA GLY A 563 −22.160 11.604 −13.726 1.00 51.84 C ATOM 1258 C GLY A 563 −20.697 11.378 −13.387 1.00 58.31 C ATOM 1259 O GLY A 563 −20.343 10.336 −12.833 1.00 56.03 O ATOM 1260 N PHE A 564 −19.843 12.342 −13.726 1.00 55.96 N ATOM 1261 CA PHE A 564 −18.411 12.245 −13.412 1.00 58.81 C ATOM 1262 C PHE A 564 −17.950 13.369 −12.476 1.00 54.14 C ATOM 1263 O PHE A 564 −16.788 13.416 −12.059 1.00 53.61 O ATOM 1264 CB PHE A 564 −17.577 12.235 −14.699 1.00 59.65 C ATOM 1265 CG PHE A 564 −17.717 10.966 −15.506 1.00 63.33 C ATOM 1266 CD2 PHE A 564 −18.454 10.947 −16.685 1.00 69.59 C ATOM 1267 CD1 PHE A 564 −17.102 9.795 −15.088 1.00 74.64 C ATOM 1268 CE2 PHE A 564 −18.573 9.786 −17.425 1.00 74.43 C ATOM 1269 CE1 PHE A 564 −17.217 8.630 −15.823 1.00 79.79 C ATOM 1270 CZ PHE A 564 −17.952 8.624 −16.992 1.00 83.51 C ATOM 1271 N ALA A 565 −18.878 14.259 −12.138 1.00 47.63 N ATOM 1272 CA ALA A 565 −18.603 15.392 −11.269 1.00 47.12 C ATOM 1273 C ALA A 565 −18.259 14.966 −9.842 1.00 56.32 C ATOM 1274 O ALA A 565 −18.648 13.887 −9.398 1.00 56.40 O ATOM 1275 CB ALA A 565 −19.783 16.351 −11.272 1.00 42.94 C ATOM 1276 N LYS A 566 −17.541 15.836 −9.134 1.00 48.04 N ATOM 1277 CA LYS A 566 −17.068 15.552 −7.777 1.00 51.73 C ATOM 1278 C LYS A 566 −17.153 16.806 −6.895 1.00 54.53 C ATOM 1279 O LYS A 566 −16.734 17.891 −7.306 1.00 51.84 O ATOM 1280 CB LYS A 566 −15.633 15.002 −7.830 1.00 57.20 C ATOM 1281 CG LYS A 566 −14.995 14.769 −6.463 1.00 77.28 C ATOM 1282 CD LYS A 566 −13.690 13.995 −6.585 1.00 89.41 C ATOM 1283 CE LYS A 566 −12.941 13.942 −5.259 1.00 88.49 C ATOM 1284 NZ LYS A 566 −12.533 15.306 −4.799 1.00 76.89 N ATOM 1285 N GLN A 567 −17.732 16.653 −5.702 1.00 54.40 N ATOM 1286 C GLN A 567 −16.485 17.591 −3.780 1.00 60.19 C ATOM 1287 O GLN A 567 −16.165 16.520 −3.247 1.00 57.51 O ATOM 1288 CA GLN A 567 −17.721 17.689 −4.673 1.00 60.39 C ATOM 1289 CB GLN A 567 −18.975 17.605 −3.784 1.00 62.20 C ATOM 1290 CG GLN A 567 −20.259 18.043 −4.482 1.00 70.67 C ATOM 1291 CD GLN A 567 −21.292 18.661 −3.539 1.00 76.68 C ATOM 1292 OE1 GLN A 567 −21.102 19.766 −3.023 1.00 84.12 O ATOM 1293 NE2 GLN A 567 −22.394 17.951 −3.320 1.00 74.69 N ATOM 1294 N LEU A 568 −15.807 18.718 −3.593 1.00 58.91 N ATOM 1295 CA LEU A 568 −14.680 18.784 −2.674 1.00 57.17 C ATOM 1296 C LEU A 568 −15.174 18.507 −1.265 1.00 66.72 C ATOM 1297 O LEU A 568 −16.110 19.153 −0.791 1.00 63.65 O ATOM 1298 CB LEU A 568 −14.066 20.176 −2.713 1.00 65.48 C ATOM 1299 CG LEU A 568 −12.843 20.398 −1.832 1.00 65.02 C ATOM 1300 CD1 LEU A 568 −11.690 19.515 −2.294 1.00 59.83 C ATOM 1301 CD2 LEU A 568 −12.455 21.867 −1.845 1.00 65.66 C ATOM 1302 N ARG A 569 −14.562 17.547 −0.587 1.00 66.91 N ATOM 1303 CA ARG A 569 −14.944 17.292 0.793 1.00 71.81 C ATOM 1304 C ARG A 569 −13.782 16.813 1.633 1.00 78.11 C ATOM 1305 O ARG A 569 −12.740 16.419 1.113 1.00 74.26 O ATOM 1306 CB ARG A 569 −16.138 16.336 0.884 1.00 84.77 C ATOM 1307 CG ARG A 569 −15.849 14.892 0.590 1.00 95.70 C ATOM 1308 CD ARG A 569 −17.107 14.070 0.804 1.00 99.08 C ATOM 1309 NE ARG A 569 −18.194 14.545 −0.046 1.00 100.93 N ATOM 1310 CZ ARG A 569 −19.357 13.921 −0.201 1.00 106.80 C ATOM 1311 NH1 ARG A 569 −19.592 12.785 0.440 1.00 112.79 N ATOM 1312 NH2 ARG A 569 −20.283 14.431 −1.003 1.00 105.02 N ATOM 1313 N ALA A 570 −13.960 16.879 2.944 1.00 72.57 N ATOM 1314 CA ALA A 570 −12.893 16.551 3.874 1.00 76.58 C ATOM 1315 C ALA A 570 −12.902 15.067 4.195 1.00 84.62 C ATOM 1316 O ALA A 570 −13.820 14.338 3.798 1.00 79.53 O ATOM 1317 CB ALA A 570 −13.054 17.361 5.153 1.00 105.03 C ATOM 1318 N GLU A 571 −11.878 14.639 4.931 1.00 85.03 N ATOM 1319 CA GLU A 571 −11.724 13.250 5.349 1.00 98.07 C ATOM 1320 C GLU A 571 −12.995 12.719 6.019 1.00 102.66 C ATOM 1321 O GLU A 571 −13.475 11.637 5.683 1.00 95.27 O ATOM 1322 CB GLU A 571 −10.527 13.118 6.297 1.00 105.29 C ATOM 1323 CG GLU A 571 −10.110 11.683 6.598 1.00 118.99 C ATOM 1324 CD GLU A 571 −9.623 11.493 8.030 1.00 130.50 C ATOM 1325 OE1 GLU A 571 −10.380 10.915 8.843 1.00 131.68 O ATOM 1326 OE2 GLU A 571 −8.486 11.912 8.344 1.00 136.05 O ATOM 1327 N ASN A 572 −13.542 13.498 6.950 1.00 108.49 N ATOM 1328 CA ASN A 572 −14.750 13.120 7.686 1.00 107.07 C ATOM 1329 C ASN A 572 −16.011 12.968 6.831 1.00 101.18 C ATOM 1330 O ASN A 572 −16.950 12.284 7.233 1.00 93.98 O ATOM 1331 CB ASN A 572 −15.009 14.107 8.828 1.00 117.49 C ATOM 1332 CG ASN A 572 −14.373 15.454 8.582 1.00 124.43 C ATOM 1333 OD1 ASN A 572 −13.353 15.551 7.904 1.00 126.22 O ATOM 1334 ND2 ASN A 572 −14.968 16.502 9.135 1.00 127.99 N ATOM 1335 N GLY A 573 −16.023 13.595 5.656 1.00 90.77 N ATOM 1336 CA GLY A 573 −17.176 13.537 4.778 1.00 92.37 C ATOM 1337 C GLY A 573 −17.813 14.900 4.575 1.00 94.91 C ATOM 1338 O GLY A 573 −18.674 15.062 3.709 1.00 84.61 O ATOM 1339 N LEU A 574 −17.372 15.878 5.367 1.00 88.53 N ATOM 1340 CA LEU A 574 −17.926 17.234 5.353 1.00 75.67 C ATOM 1341 C LEU A 574 −17.738 17.936 4.016 1.00 86.74 C ATOM 1342 O LEU A 574 −16.619 18.026 3.504 1.00 77.05 O ATOM 1343 CB LEU A 574 −17.270 18.085 6.445 1.00 78.80 C ATOM 1344 CG LEU A 574 −18.064 18.262 7.735 1.00 82.03 C ATOM 1345 CD1 LEU A 574 −17.283 19.118 8.736 1.00 85.28 C ATOM 1346 CD2 LEU A 574 −19.426 18.871 7.416 1.00 88.71 C ATOM 1347 N LEU A 575 −18.829 18.452 3.461 1.00 81.20 N ATOM 1348 CA LEU A 575 −18.741 19.230 2.242 1.00 76.18 C ATOM 1349 C LEU A 575 −17.964 20.527 2.445 1.00 70.95 C ATOM 1350 O LEU A 575 −18.118 21.216 3.447 1.00 80.30 O ATOM 1351 CB LEU A 575 −20.129 19.465 1.647 1.00 87.45 C ATOM 1352 CG LEU A 575 −20.663 18.129 1.119 1.00 95.28 C ATOM 1353 CD1 LEU A 575 −22.015 18.265 0.465 1.00 99.82 C ATOM 1354 CD2 LEU A 575 −19.670 17.524 0.147 1.00 97.21 C ATOM 1355 N MET A 576 −17.116 20.842 1.472 1.00 74.81 N ATOM 1356 CA MET A 576 −16.179 21.943 1.607 1.00 76.51 C ATOM 1357 C MET A 576 −16.169 22.799 0.335 1.00 80.73 C ATOM 1358 O MET A 576 −16.444 22.315 −0.766 1.00 70.70 O ATOM 1359 CB MET A 576 −14.781 21.382 1.865 1.00 85.50 C ATOM 1360 CG MET A 576 −13.932 22.189 2.814 1.00 96.95 C ATOM 1361 SD MET A 576 −14.569 22.149 4.499 1.00 115.63 S ATOM 1362 CE MET A 576 −14.856 20.399 4.701 1.00 122.51 C ATOM 1363 N THR A 577 −15.868 24.081 0.496 1.00 98.30 N ATOM 1364 CA THR A 577 −15.692 24.974 −0.644 1.00 99.19 C ATOM 1365 C THR A 577 −14.221 25.349 −0.681 1.00 95.27 C ATOM 1366 O THR A 577 −13.569 25.369 0.368 1.00 96.92 O ATOM 1367 CB THR A 577 −16.546 26.250 −0.503 1.00 100.21 C ATOM 1368 OG1 THR A 577 −16.010 27.081 0.537 1.00 90.26 O ATOM 1369 CG2 THR A 577 −17.997 25.897 −0.180 1.00 100.60 C ATOM 1370 N PRO A 578 −13.684 25.645 −1.876 1.00 83.35 N ATOM 1371 CA PRO A 578 −12.257 25.982 −1.961 1.00 80.34 C ATOM 1372 C PRO A 578 −11.954 27.304 −1.265 1.00 90.97 C ATOM 1373 O PRO A 578 −10.785 27.647 −1.081 1.00 99.53 O ATOM 1374 CB PRO A 578 −12.007 26.112 −3.472 1.00 70.55 C ATOM 1375 CG PRO A 578 −13.162 25.446 −4.120 1.00 67.94 C ATOM 1376 CD PRO A 578 −14.324 25.648 −3.201 1.00 73.80 C ATOM 1377 N CYS A 579 −12.996 28.036 −0.887 1.00 86.36 N ATOM 1378 CA CYS A 579 −12.816 29.288 −0.165 1.00 100.63 C ATOM 1379 C CYS A 579 −12.648 29.075 1.348 1.00 100.99 C ATOM 1380 O CYS A 579 −11.906 29.806 2.012 1.00 87.07 O ATOM 1381 CB CYS A 579 −13.983 30.236 −0.449 1.00 106.64 C ATOM 1382 SG CYS A 579 −13.589 31.968 −0.114 1.00 183.45 S ATOM 1383 N TYR A 580 −13.339 28.074 1.886 1.00 102.40 N ATOM 1384 CA TYR A 580 −13.170 27.698 3.286 1.00 108.15 C ATOM 1385 C TYR A 580 −12.816 26.222 3.416 1.00 118.71 C ATOM 1386 O TYR A 580 −13.697 25.361 3.415 1.00 121.05 O ATOM 1387 CB TYR A 580 −14.436 27.992 4.092 1.00 102.03 C ATOM 1388 CG TYR A 580 −14.308 27.673 5.570 1.00 98.77 C ATOM 1389 CD2 TYR A 580 −14.681 26.431 6.072 1.00 89.57 C ATOM 1390 CD1 TYR A 580 −13.817 28.617 6.463 1.00 103.54 C ATOM 1391 CE2 TYR A 580 −14.572 26.143 7.418 1.00 104.48 C ATOM 1392 CE1 TYR A 580 −13.704 28.336 7.815 1.00 103.38 C ATOM 1393 CZ TYR A 580 −14.081 27.098 8.286 1.00 105.34 C ATOM 1394 OH TYR A 580 −13.965 26.808 9.629 1.00 109.68 O ATOM 1395 N THR A 581 −11.522 25.938 3.520 1.00 122.25 N ATOM 1396 CA THR A 581 −11.051 24.581 3.760 1.00 119.54 C ATOM 1397 C THR A 581 −10.329 24.536 5.096 1.00 121.14 C ATOM 1398 O THR A 581 −9.456 23.696 5.320 1.00 118.96 O ATOM 1399 CB THR A 581 −10.107 24.084 2.640 1.00 113.94 C ATOM 1400 OG1 THR A 581 −9.173 25.117 2.302 1.00 123.30 O ATOM 1401 CG2 THR A 581 −10.899 23.694 1.395 1.00 90.62 C ATOM 1402 N ALA A 582 −10.718 25.436 5.995 1.00 123.46 N ATOM 1403 CA ALA A 582 −10.076 25.550 7.303 1.00 126.36 C ATOM 1404 C ALA A 582 −10.292 24.325 8.200 1.00 130.02 C ATOM 1405 O ALA A 582 −10.078 24.385 9.413 1.00 124.41 O ATOM 1406 CB ALA A 582 −10.518 26.828 8.010 1.00 125.72 C ATOM 1407 N ASN A 583 −10.730 23.224 7.594 1.00 129.78 N ATOM 1408 CA ASN A 583 −10.701 21.916 8.228 1.00 135.26 C ATOM 1409 C ASN A 583 −9.512 21.152 7.670 1.00 130.65 C ATOM 1410 O ASN A 583 −8.510 21.752 7.272 1.00 124.90 O ATOM 1411 CB ASN A 583 −11.990 21.143 7.945 1.00 133.32 C ATOM 1412 CG ASN A 583 −13.223 21.870 8.434 1.00 138.30 C ATOM 1413 OD1 ASN A 583 −13.232 23.095 8.541 1.00 144.00 O ATOM 1414 ND2 ASN A 583 −14.274 21.117 8.738 1.00 137.18 N ATOM 1415 N PHE A 584 −9.620 19.829 7.626 1.00 127.92 N ATOM 1416 CA PHE A 584 −8.585 19.032 6.984 1.00 122.55 C ATOM 1417 C PHE A 584 −9.053 18.415 5.670 1.00 107.35 C ATOM 1418 O PHE A 584 −9.850 17.472 5.654 1.00 100.95 O ATOM 1419 CB PHE A 584 −8.020 17.946 7.912 1.00 128.70 C ATOM 1420 CG PHE A 584 −7.055 17.011 7.222 1.00 128.85 C ATOM 1421 CD1 PHE A 584 −5.852 17.487 6.715 1.00 122.38 C ATOM 1422 CD2 PHE A 584 −7.356 15.665 7.066 1.00 128.23 C ATOM 1423 CE1 PHE A 584 −4.967 16.638 6.070 1.00 115.00 C ATOM 1424 CE2 PHE A 584 −6.475 14.811 6.422 1.00 123.55 C ATOM 1425 CZ PHE A 584 −5.279 15.299 5.924 1.00 117.76 C ATOM 1426 N VAL A 585 −8.560 18.973 4.569 1.00 95.84 N ATOM 1427 CA VAL A 585 −8.632 18.300 3.284 1.00 86.96 C ATOM 1428 C VAL A 585 −7.242 17.764 2.952 1.00 87.67 C ATOM 1429 O VAL A 585 −6.239 18.474 3.088 1.00 98.90 O ATOM 1430 CB VAL A 585 −9.155 19.225 2.149 1.00 117.47 C ATOM 1431 CG1 VAL A 585 −10.648 19.478 2.311 1.00 118.31 C ATOM 1432 CG2 VAL A 585 −8.383 20.538 2.104 1.00 116.04 C ATOM 1433 N ALA A 586 −7.186 16.498 2.550 1.00 82.15 N ATOM 1434 CA ALA A 586 −5.922 15.866 2.188 1.00 90.55 C ATOM 1435 C ALA A 586 −5.273 16.647 1.053 1.00 85.05 C ATOM 1436 O ALA A 586 −5.978 17.208 0.207 1.00 76.29 O ATOM 1437 CB ALA A 586 −6.154 14.417 1.780 1.00 91.08 C ATOM 1438 N PRO A 587 −3.932 16.696 1.036 1.00 90.13 N ATOM 1439 CA PRO A 587 −3.196 17.419 −0.007 1.00 87.44 C ATOM 1440 C PRO A 587 −3.527 16.901 −1.401 1.00 90.18 C ATOM 1441 O PRO A 587 −3.786 17.691 −2.318 1.00 83.80 O ATOM 1442 CB PRO A 587 −1.729 17.111 0.323 1.00 83.19 C ATOM 1443 CG PRO A 587 −1.774 15.855 1.132 1.00 94.40 C ATOM 1444 CD PRO A 587 −3.021 15.989 1.953 1.00 92.48 C ATOM 1445 N GLU A 588 −3.534 15.580 −1.547 1.00 91.91 N ATOM 1446 CA GLU A 588 −3.744 14.952 −2.847 1.00 91.75 C ATOM 1447 C GLU A 588 −5.162 15.170 −3.375 1.00 79.51 C ATOM 1448 O GLU A 588 −5.386 15.124 −4.583 1.00 77.18 O ATOM 1449 CB GLU A 588 −3.417 13.456 −2.776 1.00 99.66 C ATOM 1450 CG GLU A 588 −2.025 13.144 −2.231 1.00 117.75 C ATOM 1451 CD GLU A 588 −0.909 13.456 −3.219 1.00 128.93 C ATOM 1452 OE1 GLU A 588 −0.218 12.507 −3.648 1.00 131.62 O ATOM 1453 OE2 GLU A 588 −0.710 14.644 −3.558 1.00 131.28 O ATOM 1454 N VAL A 589 −6.111 15.411 −2.473 1.00 75.49 N ATOM 1455 CA VAL A 589 −7.494 15.685 −2.874 1.00 69.65 C ATOM 1456 C VAL A 589 −7.642 17.114 −3.395 1.00 69.40 C ATOM 1457 O VAL A 589 −8.323 17.355 −4.404 1.00 66.65 O ATOM 1458 CB VAL A 589 −8.497 15.421 −1.722 1.00 95.71 C ATOM 1459 CG1 VAL A 589 −9.888 15.942 −2.083 1.00 88.20 C ATOM 1460 CG2 VAL A 589 −8.549 13.934 −1.395 1.00 91.67 C ATOM 1461 N LEU A 590 −6.988 18.057 −2.721 1.00 78.16 N ATOM 1462 CA LEU A 590 −7.017 19.452 −3.153 1.00 79.10 C ATOM 1463 C LEU A 590 −6.297 19.638 −4.489 1.00 75.05 C ATOM 1464 O LEU A 590 −6.797 20.322 −5.386 1.00 69.24 O ATOM 1465 CB LEU A 590 −6.383 20.353 −2.092 1.00 84.90 C ATOM 1466 CG LEU A 590 −6.900 21.796 −2.063 1.00 95.70 C ATOM 1467 CD1 LEU A 590 −8.394 21.832 −1.734 1.00 97.39 C ATOM 1468 CD2 LEU A 590 −6.110 22.636 −1.063 1.00 94.55 C ATOM 1469 N GLU A 591 −5.122 19.026 −4.608 1.00 74.33 N ATOM 1470 CA GLU A 591 −4.328 19.097 −5.829 1.00 74.46 C ATOM 1471 C GLU A 591 −5.095 18.523 −7.010 1.00 67.55 C ATOM 1472 O GLU A 591 −5.150 19.127 −8.086 1.00 69.41 O ATOM 1473 CB GLU A 591 −3.023 18.329 −5.639 1.00 89.98 C ATOM 1474 CG GLU A 591 −2.142 18.269 −6.868 1.00 100.67 C ATOM 1475 CD GLU A 591 −1.370 16.964 −6.961 1.00 117.66 C ATOM 1476 OE1 GLU A 591 −1.960 15.955 −7.405 1.00 125.15 O ATOM 1477 OE2 GLU A 591 −0.179 16.944 −6.584 1.00 119.84 O ATOM 1478 N ARG A 592 −5.690 17.350 −6.811 1.00 62.99 N ATOM 1479 CA ARG A 592 −6.460 16.720 −7.871 1.00 68.24 C ATOM 1480 C ARG A 592 −7.640 17.598 −8.236 1.00 64.35 C ATOM 1481 O ARG A 592 −8.059 17.645 −9.395 1.00 55.08 O ATOM 1482 CB ARG A 592 −6.967 15.342 −7.446 1.00 82.77 C ATOM 1483 CG ARG A 592 −7.580 14.562 −8.598 1.00 99.82 C ATOM 1484 CD ARG A 592 −8.850 13.840 −8.191 1.00 112.73 C ATOM 1485 NE ARG A 592 −9.224 12.835 −9.180 1.00 117.18 N ATOM 1486 CZ ARG A 592 −8.790 11.578 −9.161 1.00 119.78 C ATOM 1487 NH1 ARG A 592 −7.968 11.173 −8.198 1.00 126.99 N ATOM 1488 NH2 ARG A 592 −9.176 10.724 −10.101 1.00 110.34 N ATOM 1489 N GLN A 593 −8.193 18.294 −7.246 1.00 54.28 N ATOM 1490 CA GLN A 593 −9.348 19.143 −7.533 1.00 56.39 C ATOM 1491 C GLN A 593 −8.953 20.364 −8.345 1.00 56.76 C ATOM 1492 O GLN A 593 −9.702 20.795 −9.217 1.00 55.93 O ATOM 1493 CB GLN A 593 −10.055 19.564 −6.259 1.00 73.64 C ATOM 1494 CG GLN A 593 −11.124 18.599 −5.857 1.00 81.23 C ATOM 1495 CD GLN A 593 −12.487 19.043 −6.308 1.00 51.73 C ATOM 1496 OE1 GLN A 593 −12.729 20.234 −6.516 1.00 74.40 O ATOM 1497 NE2 GLN A 593 −13.405 18.096 −6.430 1.00 71.53 N ATOM 1498 N GLY A 594 −7.784 20.919 −8.042 1.00 55.58 N ATOM 1499 CA GLY A 594 −7.212 21.972 −8.862 1.00 58.11 C ATOM 1500 C GLY A 594 −7.010 21.518 −10.300 1.00 50.74 C ATOM 1501 O GLY A 594 −7.381 22.230 −11.242 1.00 49.48 O ATOM 1502 N TYR A 595 −6.422 20.334 −10.472 1.00 55.75 N ATOM 1503 CA TYR A 595 −6.244 19.727 −11.796 1.00 57.81 C ATOM 1504 C TYR A 595 −7.566 19.530 −12.528 1.00 54.55 C ATOM 1505 O TYR A 595 −7.695 19.843 −13.720 1.00 47.60 O ATOM 1506 CB TYR A 595 −5.553 18.367 −11.669 1.00 60.23 C ATOM 1507 CG TYR A 595 −4.059 18.435 −11.445 1.00 61.49 C ATOM 1508 CD1 TYR A 595 −3.301 19.472 −11.976 1.00 63.68 C ATOM 1509 CD2 TYR A 595 −3.406 17.457 −10.705 1.00 61.45 C ATOM 1510 CE1 TYR A 595 −1.917 19.534 −11.771 1.00 66.70 C ATOM 1511 CE2 TYR A 595 −2.025 17.509 −10.496 1.00 68.39 C ATOM 1512 CZ TYR A 595 −1.290 18.552 −11.031 1.00 70.26 C ATOM 1513 OH TYR A 595 0.075 18.608 −10.830 1.00 74.62 O ATOM 1514 N ASP A 596 −8.547 18.977 −11.826 1.00 46.37 N ATOM 1515 CA ASP A 596 −9.852 18.741 −12.451 1.00 43.32 C ATOM 1516 C ASP A 596 −10.524 20.031 −12.915 1.00 48.95 C ATOM 1517 O ASP A 596 −11.133 20.056 −13.992 1.00 41.86 O ATOM 1518 CB ASP A 596 −10.789 17.980 −11.504 1.00 62.25 C ATOM 1519 CG ASP A 596 −10.443 16.503 −11.388 1.00 69.13 C ATOM 1520 OD1 ASP A 596 −9.778 15.967 −12.294 1.00 66.47 O ATOM 1521 OD2 ASP A 596 −10.852 15.874 −10.394 1.00 66.88 O ATOM 1522 N ALA A 597 −10.444 21.083 −12.097 1.00 50.34 N ATOM 1523 CA ALA A 597 −11.049 22.369 −12.454 1.00 45.57 C ATOM 1524 C ALA A 597 −10.353 22.983 −13.667 1.00 45.67 C ATOM 1525 O ALA A 597 −11.001 23.546 −14.535 1.00 43.11 O ATOM 1526 CB ALA A 597 −11.005 23.334 −11.275 1.00 45.23 C ATOM 1527 N ALA A 598 −9.028 22.866 −13.719 1.00 45.37 N ATOM 1528 CA ALA A 598 −8.284 23.323 −14.892 1.00 42.10 C ATOM 1529 C ALA A 598 −8.695 22.562 −16.139 1.00 42.16 C ATOM 1530 O ALA A 598 −8.701 23.120 −17.234 1.00 44.71 O ATOM 1531 CB ALA A 598 −6.783 23.146 −14.660 1.00 47.75 C ATOM 1532 N CYS A 599 −9.001 21.276 −15.985 1.00 45.10 N ATOM 1533 CA CYS A 599 −9.384 20.462 −17.136 1.00 39.69 C ATOM 1534 C CYS A 599 −10.748 20.924 −17.631 1.00 40.49 C ATOM 1535 O CYS A 599 −11.002 20.967 −18.846 1.00 39.90 O ATOM 1536 CB CYS A 599 −9.420 18.975 −16.779 1.00 54.65 C ATOM 1537 SG CYS A 599 −9.642 17.893 −18.221 1.00 64.69 S ATOM 1538 N ASP A 600 −11.622 21.293 −16.696 1.00 37.31 N ATOM 1539 CA ASP A 600 −12.921 21.883 −17.076 1.00 34.04 C ATOM 1540 C ASP A 600 −12.712 23.115 −17.969 1.00 40.71 C ATOM 1541 O ASP A 600 −13.413 23.306 −18.954 1.00 39.80 O ATOM 1542 CB ASP A 600 −13.721 22.350 −15.843 1.00 42.30 C ATOM 1543 CG ASP A 600 −14.450 21.213 −15.105 1.00 46.72 C ATOM 1544 OD1 ASP A 600 −14.522 20.079 −15.618 1.00 43.07 O ATOM 1545 OD2 ASP A 600 −14.970 21.482 −13.987 1.00 46.92 O ATOM 1546 N ILE A 601 −11.786 23.988 −17.578 1.00 42.81 N ATOM 1547 CA ILE A 601 −11.541 25.212 −18.344 1.00 43.69 C ATOM 1548 C ILE A 601 −10.938 24.894 −19.720 1.00 39.83 C ATOM 1549 O ILE A 601 −11.266 25.540 −20.720 1.00 38.17 O ATOM 1550 CB ILE A 601 −10.588 26.198 −17.598 1.00 43.79 C ATOM 1551 CG1 ILE A 601 −11.162 26.590 −16.224 1.00 45.62 C ATOM 1552 CG2 ILE A 601 −10.322 27.436 −18.455 1.00 43.73 C ATOM 1553 CD1 ILE A 601 −12.677 26.973 −16.279 1.00 46.88 C ATOM 1554 N TRP A 602 −10.045 23.906 −19.771 1.00 40.40 N ATOM 1555 CA TRP A 602 −9.461 23.480 −21.043 1.00 38.37 C ATOM 1556 C TRP A 602 −10.553 23.059 −22.042 1.00 43.03 C ATOM 1557 O TRP A 602 −10.508 23.416 −23.237 1.00 38.59 O ATOM 1558 CB TRP A 602 −8.463 22.335 −20.779 1.00 36.70 C ATOM 1559 CG TRP A 602 −7.741 21.803 −22.014 1.00 40.99 C ATOM 1560 CD1 TRP A 602 −6.523 22.213 −22.506 1.00 42.29 C ATOM 1561 CD2 TRP A 602 −8.183 20.740 −22.872 1.00 39.62 C ATOM 1562 NE1 TRP A 602 −6.202 21.479 −23.643 1.00 39.75 N ATOM 1563 CE2 TRP A 602 −7.198 20.558 −23.876 1.00 38.52 C ATOM 1564 CE3 TRP A 602 −9.318 19.913 −22.893 1.00 41.60 C ATOM 1565 CZ2 TRP A 602 −7.303 19.586 −24.875 1.00 40.29 C ATOM 1566 CZ3 TRP A 602 −9.431 18.955 −23.892 1.00 47.49 C ATOM 1567 CH2 TRP A 602 −8.431 18.802 −24.870 1.00 50.05 C ATOM 1568 N SER A 603 −11.555 22.326 −21.556 1.00 40.07 N ATOM 1569 CA SER A 603 −12.659 21.924 −22.439 1.00 41.40 C ATOM 1570 C SER A 603 −13.492 23.101 −22.937 1.00 38.42 C ATOM 1571 O SER A 603 −14.011 23.071 −24.048 1.00 36.41 O ATOM 1572 CB SER A 603 −13.580 20.897 −21.781 1.00 39.90 C ATOM 1573 OG SER A 603 −12.946 19.630 −21.757 1.00 47.31 O ATOM 1574 N LEU A 604 −13.639 24.126 −22.109 1.00 35.38 N ATOM 1575 CA LEU A 604 −14.314 25.342 −22.578 1.00 34.44 C ATOM 1576 C LEU A 604 −13.422 26.032 −23.610 1.00 39.36 C ATOM 1577 O LEU A 604 −13.910 26.684 −24.535 1.00 40.12 O ATOM 1578 CB LEU A 604 −14.612 26.277 −21.389 1.00 32.55 C ATOM 1579 CG LEU A 604 −15.560 25.753 −20.307 1.00 42.45 C ATOM 1580 CD1 LEU A 604 −15.781 26.821 −19.233 1.00 42.37 C ATOM 1581 CD2 LEU A 604 −16.893 25.337 −20.926 1.00 38.42 C ATOM 1582 N GLY A 605 −12.107 25.894 −23.453 1.00 37.05 N ATOM 1583 CA GLY A 605 −11.192 26.380 −24.484 1.00 36.81 C ATOM 1584 C GLY A 605 −11.390 25.664 −25.815 1.00 33.89 C ATOM 1585 O GLY A 605 −11.399 26.289 −26.886 1.00 38.11 O ATOM 1586 N VAL A 605 −11.551 24.347 −25.762 1.00 32.85 N ATOM 1587 CA VAL A 606 −11.788 23.566 −26.976 1.00 37.30 C ATOM 1588 C VAL A 606 −13.099 24.010 −27.620 1.00 39.21 C ATOM 1589 O VAL A 606 −13.205 24.140 −28.837 1.00 36.02 O ATOM 1590 CB VAL A 606 −11.876 22.060 −26.657 1.00 33.15 C ATOM 1591 CG1 VAL A 606 −12.374 21.284 −27.895 1.00 36.87 C ATOM 1592 CG2 VAL A 606 −10.496 21.551 −26.234 1.00 38.89 C ATOM 1593 N LEU A 607 −14.093 24.237 −26.776 1.00 31.77 N ATOM 1594 CA LEU A 607 −15.379 24.758 −27.245 1.00 34.96 C ATOM 1595 C LEU A 607 −15.198 26.087 −27.970 1.00 34.74 C ATOM 1596 O LEU A 607 −15.711 26.283 −29.063 1.00 35.94 O ATOM 1597 CB LEU A 607 −16.333 24.935 −26.063 1.00 34.20 C ATOM 1598 CG LEU A 607 −17.713 25.530 −26.417 1.00 34.74 C ATOM 1599 CD1 LEU A 607 −18.473 24.576 −27.302 1.00 39.28 C ATOM 1600 CD2 LEU A 607 −18.504 25.808 −25.131 1.00 43.29 C ATOM 1601 N LEU A 608 −14.452 26.998 −27.364 1.00 37.23 N ATOM 1602 CA LEU A 608 −14.299 28.331 −27.922 1.00 38.33 C ATOM 1603 C LEU A 608 −13.599 28.283 −29.269 1.00 38.75 C ATOM 1604 O LEU A 608 −14.043 28.898 −30.250 1.00 38.48 O ATOM 1605 CB LEU A 608 −13.487 29.204 −26.950 1.00 35.49 C ATOM 1606 CG LEU A 608 −13.222 30.623 −27.466 1.00 39.61 C ATOM 1607 CD1 LEU A 608 −14.537 31.282 −27.856 1.00 40.71 C ATOM 1608 CD2 LEU A 608 −12.501 31.463 −26.412 1.00 41.53 C ATOM 1609 N TYR A 609 −12.480 27.565 −29.305 1.00 42.21 N ATOM 1610 CA TYR A 609 −11.697 27.397 −30.528 1.00 41.67 C ATOM 1611 C TYR A 609 −12.616 26.969 −31.670 1.00 41.87 C ATOM 1612 O TYR A 609 −12.604 27.533 −32.780 1.00 40.73 O ATOM 1613 CB TYR A 609 −10.618 26.320 −30.284 1.00 36.02 C ATOM 1614 CG TYR A 609 −9.573 26.195 −31.382 1.00 38.82 C ATOM 1615 CD1 TYR A 609 −9.875 25.607 −32.620 1.00 40.85 C ATOM 1616 CD2 TYR A 609 −8.287 26.661 −31.181 1.00 43.06 C ATOM 1617 CE1 TYR A 609 −8.908 25.501 −33.620 1.00 41.34 C ATOM 1618 CE2 TYR A 609 −7.324 26.545 −32.152 1.00 37.60 C ATOM 1619 CZ TYR A 609 −7.639 25.971 −33.373 1.00 45.12 C ATOM 1620 OH TYR A 609 −6.669 25.874 −34.334 1.00 47.50 O ATOM 1621 N THR A 610 −13.426 25.959 −31.395 1.00 34.97 N ATOM 1622 CA THR A 610 −14.273 25.364 −32.421 1.00 39.28 C ATOM 1623 C THR A 610 −15.412 26.308 −32.842 1.00 41.33 C ATOM 1624 O THR A 610 −15.728 26.405 −34.025 1.00 38.62 O ATOM 1625 CB THR A 610 −14.864 24.023 −31.929 1.00 37.72 C ATOM 1626 OG1 THR A 610 −13.805 23.176 −31.483 1.00 38.73 O ATOM 1627 CG2 THR A 610 −15.623 23.306 −33.062 1.00 36.30 C ATOM 1628 N MET A 611 −16.019 27.010 −31.878 1.00 36.84 N ATOM 1629 CA MET A 611 −17.049 28.007 −32.208 1.00 36.11 C ATOM 1630 C MET A 611 −16.498 29.077 −33.124 1.00 41.78 C ATOM 1631 O MET A 611 −17.187 29.545 −34.035 1.00 39.78 O ATOM 1632 CB MET A 611 −17.558 28.701 −30.927 1.00 38.29 C ATOM 1633 CG MET A 611 −18.547 27.899 −30.107 1.00 46.31 C ATOM 1634 SD MET A 611 −19.386 28.981 −28.905 1.00 46.99 S ATOM 1635 CE MET A 611 −18.000 29.407 −27.841 1.00 44.33 C ATOM 1636 N LEU A 612 −15.249 29.482 −32.885 1.00 34.51 N ATOM 1637 CA LEU A 612 −14.683 30.576 −33.677 1.00 41.20 C ATOM 1638 C LEU A 612 −14.320 30.200 −35.119 1.00 47.98 C ATOM 1639 O LEU A 612 −14.400 31.038 −36.004 1.00 47.57 O ATOM 1640 CB LEU A 612 −13.445 31.157 −32.989 1.00 37.71 C ATOM 1641 CG LEU A 612 −13.705 31.831 −31.632 1.00 45.18 C ATOM 1642 CD1 LEU A 612 −12.394 32.222 −30.916 1.00 44.55 C ATOM 1643 CD2 LEU A 612 −14.608 33.041 −31.834 1.00 53.20 C ATOM 1644 N THR A 613 −13.901 28.959 −35.356 1.00 40.03 N ATOM 1645 CA THR A 613 −13.348 28.598 −36.669 1.00 41.06 C ATOM 1646 C THR A 613 −14.053 27.457 −37.385 1.00 49.27 C ATOM 1647 O THR A 613 −13.802 27.217 −38.565 1.00 42.00 O ATOM 1648 CB THR A 613 −11.900 28.144 −36.535 1.00 50.70 C ATOM 1649 OG1 THR A 613 −11.857 26.992 −35.676 1.00 41.83 O ATOM 1650 CG2 THR A 613 −11.067 29.248 −35.955 1.00 51.99 C ATOM 1651 N GLY A 614 −14.891 26.719 −36.672 1.00 40.55 N ATOM 1652 CA GLY A 614 −15.555 25.576 −37.279 1.00 40.35 C ATOM 1653 C GLY A 614 −14.735 24.291 −37.362 1.00 43.18 C ATOM 1654 O GLY A 614 −15.154 23.330 −38.000 1.00 41.14 O ATOM 1655 N TYR A 615 −13.554 24.265 −36.751 1.00 35.81 N ATOM 1656 CA TYR A 615 −12.817 22.998 −36.609 1.00 47.32 C ATOM 1657 C TYR A 615 −12.200 22.909 −35.218 1.00 40.59 C ATOM 1658 O TYR A 615 −12.087 23.923 −34.536 1.00 36.64 O ATOM 1659 CB TYR A 615 −11.772 22.810 −37.723 1.00 48.08 C ATOM 1660 CG TYR A 615 −10.642 23.813 −37.702 1.00 47.10 C ATOM 1661 CD2 TYR A 615 −9.424 23.511 −37.095 1.00 44.54 C ATOM 1662 CD1 TYR A 615 −10.775 25.052 −38.320 1.00 58.12 C ATOM 1663 CE2 TYR A 615 −8.373 24.432 −37.083 1.00 48.95 C ATOM 1664 CE1 TYR A 615 −9.733 25.976 −38.316 1.00 61.51 C ATOM 1665 CZ TYR A 615 −8.538 25.662 −37.694 1.00 53.99 C ATOM 1666 OH TYR A 615 −7.505 26.577 −37.690 1.00 59.16 O ATOM 1667 N THR A 616 −11.840 21.705 −34.777 1.00 41.60 N ATOM 1668 CA THR A 616 −11.407 21.520 −33.398 1.00 36.21 C ATOM 1669 C THR A 616 −9.878 21.630 −33.343 1.00 37.56 C ATOM 1670 O THR A 616 −9.207 21.332 −34.319 1.00 38.77 O ATOM 1671 CB THR A 616 −11.850 20.164 −32.802 1.00 42.19 C ATOM 1672 OG1 THR A 616 −10.912 19.148 −33.175 1.00 44.77 O ATOM 1673 CG2 THR A 616 −13.241 19.777 −33.288 1.00 38.05 C ATOM 1674 N PRO A 617 −9.339 22.067 −32.199 1.00 35.63 N ATOM 1675 CA PRO A 617 −7.898 22.386 −32.180 1.00 35.60 C ATOM 1676 C PRO A 617 −6.927 21.220 −32.313 1.00 41.74 C ATOM 1677 O PRO A 617 −5.765 21.444 −32.703 1.00 41.40 O ATOM 1678 CB PRO A 617 −7.702 23.039 −30.811 1.00 40.50 C ATOM 1679 CG PRO A 617 −8.896 22.601 −29.975 1.00 41.15 C ATOM 1680 CD PRO A 617 −10.020 22.522 −30.976 1.00 36.88 C ATOM 1681 N PHE A 618 −7.344 20.009 −31.954 1.00 37.89 N ATOM 1682 CA PHE A 618 −6.379 18.898 −31.875 1.00 41.43 C ATOM 1683 C PHE A 618 −6.725 17.699 −32.736 1.00 45.00 C ATOM 1684 O PHE A 618 −6.032 16.687 −32.705 1.00 39.01 O ATOM 1685 CB PHE A 618 −6.218 18.458 −30.420 1.00 39.79 C ATOM 1686 CG PHE A 618 −5.808 19.580 −29.500 1.00 37.50 C ATOM 1687 CD1 PHE A 618 −4.530 20.116 −29.591 1.00 43.67 C ATOM 1688 CD2 PHE A 618 −6.697 20.100 −28.573 1.00 42.43 C ATOM 1689 CE1 PHE A 618 −4.128 21.146 −28.753 1.00 44.11 C ATOM 1690 CE2 PHE A 618 −6.318 21.144 −27.731 1.00 41.53 C ATOM 1691 CZ PHE A 618 −5.012 21.662 −27.823 1.00 41.24 C ATOM 1692 N ALA A 619 −7.808 17.791 −33.496 1.00 37.40 N ATOM 1693 CA ALA A 619 −8.158 16.679 −34.373 1.00 45.31 C ATOM 1694 C ALA A 619 −8.916 17.170 −35.597 1.00 42.16 C ATOM 1695 O ALA A 619 −9.764 18.056 −35.486 1.00 44.07 O ATOM 1696 CB ALA A 619 −8.981 15.641 −33.609 1.00 40.24 C ATOM 1697 N ASN A 620 −8.623 16.575 −36.751 1.00 39.96 N ATOM 1698 CA ASN A 620 −9.236 16.998 −38.015 1.00 45.12 C ATOM 1699 C ASN A 620 −10.507 16.231 −38.372 1.00 51.28 C ATOM 1700 O ASN A 620 −11.299 16.672 −39.210 1.00 56.42 O ATOM 1701 CB ASN A 620 −8.227 16.908 −39.156 1.00 51.26 C ATOM 1702 CG ASN A 620 −7.146 17.961 −39.047 1.00 61.71 C ATOM 1703 OD1 ASN A 620 −7.429 19.126 −38.751 1.00 65.77 O ATOM 1704 ND2 ASN A 620 −5.901 17.558 −39.261 1.00 59.28 N ATOM 1705 N GLY A 621 −10.705 15.094 −37.717 1.00 47.09 N ATOM 1706 CA GLY A 621 −11.819 14.218 −38.032 1.00 46.86 C ATOM 1707 C GLY A 621 −11.792 12.997 −37.139 1.00 51.13 C ATOM 1708 O GLY A 621 −10.860 12.843 −36.339 1.00 48.36 O ATOM 1709 N PRO A 622 −12.802 12.116 −37.282 1.00 47.62 N ATOM 1710 CA PRO A 622 −13.002 10.948 −36.410 1.00 47.47 C ATOM 1711 C PRO A 622 −11.902 9.890 −36.561 1.00 51.65 C ATOM 1712 O PRO A 622 −11.720 9.059 −35.670 1.00 58.12 O ATOM 1713 CB PRO A 622 −14.341 10.375 −36.896 1.00 54.68 C ATOM 1714 CG PRO A 622 −14.425 10.791 −38.339 1.00 51.36 C ATOM 1715 CD PRO A 622 −13.761 12.146 −38.407 1.00 51.93 C ATOM 1716 N ASP A 623 −11.176 9.932 −37.670 1.00 50.49 N ATOM 1717 CA ASP A 623 −10.140 8.937 −37.938 1.00 53.31 C ATOM 1718 C ASP A 623 −8.738 9.301 −37.437 1.00 48.66 C ATOM 1719 O ASP A 623 −7.813 8.520 −37.607 1.00 55.02 O ATOM 1720 CB ASP A 623 −10.063 8.630 −39.434 1.00 55.94 C ATOM 1721 CG ASP A 623 −11.350 8.057 −39.975 1.00 69.27 C ATOM 1722 OD1 ASP A 623 −12.088 7.414 −39.193 1.00 67.92 O ATOM 1723 OD2 ASP A 623 −11.618 8.251 −41.182 1.00 70.23 O ATOM 1724 N ASP A 624 −8.570 10.480 −36.852 1.00 53.76 N ATOM 1725 CA ASP A 624 −7.271 10.841 −36.279 1.00 57.84 C ATOM 1726 C ASP A 624 −6.872 9.841 −35.189 1.00 53.13 C ATOM 1727 O ASP A 624 −7.676 9.485 −34.331 1.00 58.46 O ATOM 1728 CB ASP A 624 −7.297 12.278 −35.730 1.00 42.91 C ATOM 1729 CG ASP A 624 −7.124 13.329 −36.830 1.00 51.74 C ATOM 1730 OD1 ASP A 624 −7.236 12.970 −38.024 1.00 61.63 O ATOM 1731 OD2 ASP A 624 −6.867 14.510 −36.501 1.00 50.02 O ATOM 1732 N THR A 625 −5.629 9.373 −35.230 1.00 51.51 N ATOM 1733 CA THR A 625 −5.170 8.425 −34.221 1.00 50.85 C ATOM 1734 C THR A 625 −5.144 9.097 −32.856 1.00 48.47 C ATOM 1735 O THR A 625 −4.941 10.308 −32.759 1.00 48.12 O ATOM 1736 CB THR A 625 −3.760 7.876 −34.565 1.00 57.39 C ATOM 1737 OG1 THR A 625 −2.802 8.934 −34.483 1.00 57.49 O ATOM 1738 CG2 THR A 625 −3.736 7.296 −35.966 1.00 54.74 C ATOM 1739 N PRO A 626 −5.359 8.323 −31.784 1.00 63.26 N ATOM 1740 CA PRO A 626 −5.284 8.901 −30.438 1.00 56.91 C ATOM 1741 C PRO A 626 −3.858 9.391 −30.127 1.00 49.12 C ATOM 1742 O PRO A 626 −3.656 10.363 −29.392 1.00 49.12 O ATOM 1743 CB PRO A 626 −5.640 7.722 −29.528 1.00 65.46 C ATOM 1744 CG PRO A 626 −6.265 6.703 −30.419 1.00 66.88 C ATOM 1745 CD PRO A 626 −5.661 6.884 −31.759 1.00 63.60 C ATOM 1746 N GLU A 627 −2.871 8.709 −30.684 1.00 51.67 N ATOM 1747 CA GLU A 627 −1.500 9.134 −30.464 1.00 57.04 C ATOM 1748 C GLU A 627 −1.228 10.515 −31.055 1.00 62.40 C ATOM 1749 O GLU A 627 −0.584 11.337 −30.409 1.00 52.50 O ATOM 1750 CB GLU A 627 −0.506 8.105 −30.998 1.00 61.81 C ATOM 1751 CG GLU A 627 −0.521 6.791 −30.252 1.00 73.05 C ATOM 1752 CD GLU A 627 −1.576 5.831 −30.764 1.00 77.19 C ATOM 1753 OE1 GLU A 627 −2.341 6.198 −31.678 1.00 75.58 O ATOM 1754 OE2 GLU A 627 −1.635 4.695 −30.255 1.00 94.64 O ATOM 1755 N GLU A 628 −1.725 10.794 −32.261 1.00 58.33 N ATOM 1756 CA GLU A 628 −1.438 12.101 −32.840 1.00 50.13 C ATOM 1757 C GLU A 628 −2.207 13.204 −32.159 1.00 46.32 C ATOM 1758 O GLU A 628 −1.721 14.325 −32.049 1.00 48.46 O ATOM 1759 CB GLU A 628 −1.619 12.140 −34.359 1.00 61.17 C ATOM 1760 CG GLU A 628 −3.019 12.009 −34.870 1.00 56.88 C ATOM 1761 CD GLU A 628 −3.017 11.778 −36.374 1.00 74.14 C ATOM 1762 OE1 GLU A 628 −3.942 11.116 −36.886 1.00 63.22 O ATOM 1763 OE2 GLU A 628 −2.068 12.245 −37.041 1.00 87.70 O ATOM 1764 N ILE A 629 −3.418 12.888 −31.712 1.00 44.92 N ATOM 1765 CA ILE A 629 −4.203 13.854 −30.969 1.00 47.51 C ATOM 1766 C ILE A 629 −3.496 14.207 −29.662 1.00 54.71 C ATOM 1767 O ILE A 629 −3.332 15.384 −29.339 1.00 44.71 O ATOM 1768 CB ILE A 629 −5.610 13.302 −30.685 1.00 43.99 C ATOM 1769 CG1 ILE A 629 −6.401 13.198 −31.998 1.00 41.00 C ATOM 1770 CG2 ILE A 629 −6.340 14.161 −29.673 1.00 39.55 C ATOM 1771 CD1 ILE A 629 −7.750 12.510 −31.804 1.00 45.24 C ATOM 1772 N LEU A 630 −3.065 13.187 −28.924 1.00 44.82 N ATOM 1773 CA LEU A 630 −2.410 13.409 −27.631 1.00 54.12 C ATOM 1774 C LEU A 630 −1.060 14.090 −27.828 1.00 51.99 C ATOM 1775 O LEU A 630 −0.622 14.881 −26.992 1.00 55.23 O ATOM 1776 CB LEU A 630 −2.222 12.084 −26.888 1.00 56.06 C ATOM 1777 CG LEU A 630 −3.509 11.487 −26.311 1.00 59.29 C ATOM 1778 CD1 LEU A 630 −3.249 10.101 −25.745 1.00 65.17 C ATOM 1779 CD2 LEU A 630 −4.074 12.417 −25.238 1.00 52.05 C ATOM 1780 N ALA A 631 −0.415 13.787 −28.948 1.00 48.06 N ATOM 1781 CA ALA A 631 0.870 14.407 −29.276 1.00 49.42 C ATOM 1782 C ALA A 631 0.667 15.907 −29.463 1.00 61.57 C ATOM 1783 O ALA A 631 1.445 16.705 −28.950 1.00 54.26 O ATOM 1784 CB ALA A 631 1.471 13.781 −30.520 1.00 61.50 C ATOM 1785 N ARG A 632 −0.400 16.288 −30.167 1.00 45.32 N ATOM 1786 CA ARG A 632 −0.746 17.699 −30.331 1.00 44.69 C ATOM 1787 C ARG A 632 −1.099 18.395 −29.015 1.00 49.06 C ATOM 1788 O ARG A 632 −0.600 19.487 −28.732 1.00 57.94 O ATOM 1789 CB ARG A 632 −1.918 17.853 −31.295 1.00 41.79 C ATOM 1790 CG ARG A 632 −1.580 17.475 −32.722 1.00 45.58 C ATOM 1791 CD ARG A 632 −2.859 17.233 −33.504 1.00 43.74 C ATOM 1792 NE ARG A 632 −2.568 16.711 −34.831 1.00 51.29 N ATOM 1793 CZ ARG A 632 −3.416 15.985 −35.551 1.00 61.59 C ATOM 1794 NH1 ARG A 632 −4.618 15.671 −35.063 1.00 44.14 N ATOM 1795 NH2 ARG A 632 −3.054 15.566 −36.749 1.00 60.04 N ATOM 1796 N ILE A 633 −1.990 17.777 −28.239 1.00 46.55 N ATOM 1797 CA ILE A 633 −2.345 18.283 −26.916 1.00 46.10 C ATOM 1798 C ILE A 633 −1.092 18.488 −26.051 1.00 56.85 C ATOM 1799 O ILE A 633 −0.871 19.577 −25.527 1.00 60.44 O ATOM 1800 CB ILE A 633 −3.329 17.344 −26.205 1.00 47.27 C ATOM 1801 CG1 ILE A 633 −4.655 17.305 −26.978 1.00 42.72 C ATOM 1802 CG2 ILE A 633 −3.553 17.796 −24.740 1.00 42.26 C ATOM 1803 CD1 ILE A 633 −5.639 16.259 −26.484 1.00 48.80 C ATOM 1804 N GLY A 634 −0.261 17.452 −25.946 1.00 49.76 N ATOM 1805 CA GLY A 634 0.926 17.491 −25.104 1.00 53.13 C ATOM 1806 C GLY A 634 1.948 18.537 −25.507 1.00 63.85 C ATOM 1807 O GLY A 634 2.716 19.028 −24.677 1.00 68.73 O ATOM 1808 N SER A 635 1.966 18.889 −26.786 1.00 67.12 N ATOM 1809 CA SER A 635 2.924 19.875 −27.281 1.00 81.45 C ATOM 1810 C SER A 635 2.477 21.290 −26.928 1.00 75.64 C ATOM 1811 O SER A 635 3.236 22.245 −27.081 1.00 77.57 O ATOM 1812 CB SER A 635 3.076 19.757 −28.797 1.00 80.11 C ATOM 1813 OG SER A 635 1.928 20.283 −29.444 1.00 70.08 O ATOM 1814 N GLY A 636 1.230 21.418 −26.485 1.00 67.99 N ATOM 1815 CA GLY A 636 0.656 22.715 −26.177 1.00 82.88 C ATOM 1816 C GLY A 636 0.624 23.665 −27.362 1.00 86.28 C ATOM 1817 O GLY A 636 0.681 24.885 −27.195 1.00 83.58 O ATOM 1818 N LYS A 637 0.532 23.109 −28.565 1.00 82.89 N ATOM 1819 CA LYS A 637 0.540 23.932 −29.767 1.00 83.06 C ATOM 1820 C LYS A 637 −0.674 23.696 −30.670 1.00 85.04 C ATOM 1821 O LYS A 637 −1.130 22.565 −30.872 1.00 78.76 O ATOM 1822 CB LYS A 637 1.854 23.760 −30.539 1.00 93.82 C ATOM 1823 CG LYS A 637 3.077 24.348 −29.832 1.00 98.01 C ATOM 1824 CD LYS A 637 3.226 25.843 −30.091 1.00 99.04 C ATOM 1825 CE LYS A 637 4.393 26.428 −29.304 1.00 103.04 C ATOM 1826 NZ LYS A 637 5.668 25.698 −29.557 1.00 108.66 N ATOM 1827 N PHE A 638 −1.188 24.795 −31.204 1.00 81.65 N ATOM 1828 CA PHE A 638 −2.398 24.797 −32.005 1.00 70.28 C ATOM 1829 C PHE A 638 −2.359 26.113 −32.774 1.00 74.22 C ATOM 1830 O PHE A 638 −1.810 27.101 −32.282 1.00 74.38 O ATOM 1831 CB PHE A 638 −3.631 24.714 −31.090 1.00 49.74 C ATOM 1832 CG PHE A 638 −3.505 25.543 −29.847 1.00 57.12 C ATOM 1833 CD2 PHE A 638 −3.040 24.982 −28.667 1.00 56.30 C ATOM 1834 CD1 PHE A 638 −3.825 26.891 −29.861 1.00 56.39 C ATOM 1835 CE2 PHE A 638 −2.896 25.746 −27.529 1.00 59.45 C ATOM 1836 CE1 PHE A 638 −3.692 27.658 −28.718 1.00 55.61 C ATOM 1837 CZ PHE A 638 −3.221 27.086 −27.554 1.00 64.35 C ATOM 1838 N SER A 639 −2.914 26.133 −33.980 1.00 64.58 N ATOM 1839 CA SER A 639 −2.795 27.319 −34.824 1.00 66.54 C ATOM 1840 C SER A 639 −3.786 28.411 −34.442 1.00 54.44 C ATOM 1841 O SER A 639 −4.962 28.133 −34.189 1.00 52.83 O ATOM 1842 CB SER A 639 −2.984 26.955 −36.297 1.00 74.31 C ATOM 1843 OG SER A 639 −3.038 28.125 −37.087 1.00 84.99 O ATOM 1844 N LEU A 640 −3.318 29.656 −34.408 1.00 45.72 N ATOM 1845 CA LEU A 640 −4.218 30.782 −34.184 1.00 51.12 C ATOM 1846 C LEU A 640 −4.031 31.849 −35.245 1.00 54.88 C ATOM 1847 O LEU A 640 −4.370 33.011 −35.031 1.00 56.32 O ATOM 1848 CB LEU A 640 −3.995 31.399 −32.809 1.00 47.12 C ATOM 1849 CG LEU A 640 −4.381 30.540 −31.610 1.00 54.66 C ATOM 1850 CD1 LEU A 640 −4.042 31.282 −30.329 1.00 62.48 C ATOM 1851 CD2 LEU A 640 −5.852 30.197 −31.670 1.00 53.46 C ATOM 1852 N SER A 641 −3.496 31.454 −36.394 1.00 50.66 N ATOM 1853 CA SER A 641 −3.197 32.410 −37.435 1.00 51.69 C ATOM 1854 C SER A 641 −3.482 31.792 −38.792 1.00 69.42 C ATOM 1855 O SER A 641 −3.400 30.577 −38.958 1.00 70.57 O ATOM 1856 CB SER A 641 −1.723 32.846 −37.355 1.00 62.23 C ATOM 1857 OG SER A 641 −1.433 33.882 −38.277 1.00 89.87 O ATOM 1858 N GLY A 642 −3.819 32.636 −39.760 1.00 72.46 N ATOM 1859 CA GLY A 642 −4.095 32.172 −41.105 1.00 68.07 C ATOM 1860 C GLY A 642 −5.486 31.599 −41.292 1.00 60.40 C ATOM 1861 O GLY A 642 −6.186 31.297 −40.322 1.00 57.26 O ATOM 1862 N GLY A 643 −5.874 31.460 −42.555 1.00 67.88 N ATOM 1863 CA GLY A 643 −7.126 30.843 −42.942 1.00 72.09 C ATOM 1864 C GLY A 643 −8.343 31.421 −42.257 1.00 60.17 C ATOM 1865 O GLY A 643 −8.646 32.610 −42.380 1.00 72.29 O ATOM 1866 N TYR A 644 −9.035 30.558 −41.523 1.00 56.14 N ATOM 1867 CA TYR A 644 −10.231 30.929 −40.790 1.00 56.29 C ATOM 1868 C TYR A 644 −9.938 31.858 −39.623 1.00 60.20 C ATOM 1869 O TYR A 644 −10.846 32.485 −39.088 1.00 67.82 O ATOM 1870 CB TYR A 644 −10.947 29.667 −40.302 1.00 51.35 C ATOM 1871 CG TYR A 644 −11.372 28.758 −41.442 1.00 59.52 C ATOM 1872 CD2 TYR A 644 −10.894 27.458 −41.533 1.00 66.72 C ATOM 1873 CD1 TYR A 644 −12.244 29.209 −42.430 1.00 63.70 C ATOM 1874 CE2 TYR A 644 −11.276 26.627 −42.566 1.00 67.51 C ATOM 1875 CE1 TYR A 644 −12.634 28.379 −43.477 1.00 65.36 C ATOM 1876 CZ TYR A 644 −12.143 27.090 −43.538 1.00 70.37 C ATOM 1877 OH TYR A 644 −12.522 26.261 −44.566 1.00 72.27 O ATOM 1878 N TRP A 645 −8.673 31.953 −39.230 1.00 62.51 N ATOM 1879 CA TRP A 645 −8.301 32.818 −38.111 1.00 57.05 C ATOM 1880 C TRP A 645 −8.035 34.265 −38.556 1.00 64.36 C ATOM 1881 O TRP A 645 −7.883 35.157 −37.720 1.00 63.24 O ATOM 1882 CB TRP A 645 −7.084 32.264 −37.361 1.00 53.21 C ATOM 1883 CG TRP A 645 −7.390 31.108 −36.455 1.00 51.15 C ATOM 1884 CD1 TRP A 645 −7.083 29.799 −36.674 1.00 50.46 C ATOM 1885 CD2 TRP A 645 −8.062 31.158 −35.192 1.00 47.73 C ATOM 1886 NE1 TRP A 645 −7.523 29.028 −35.632 1.00 53.02 N ATOM 1887 CE2 TRP A 645 −8.120 29.836 −34.701 1.00 47.51 C ATOM 1888 CE3 TRP A 645 −8.620 32.189 −34.427 1.00 48.85 C ATOM 1889 CZ2 TRP A 645 −8.718 29.515 −33.484 1.00 44.73 C ATOM 1890 CZ3 TRP A 645 −9.218 31.867 −33.208 1.00 50.16 C ATOM 1891 CH2 TRP A 645 −9.259 30.539 −32.750 1.00 47.68 C ATOM 1892 N ASN A 646 −7.983 34.501 −39.863 1.00 69.85 N ATOM 1893 CA ASN A 646 −7.709 35.843 −40.374 1.00 74.04 C ATOM 1894 C ASN A 646 −8.775 36.878 −40.012 1.00 72.60 C ATOM 1895 O ASN A 646 −8.474 38.060 −39.851 1.00 81.41 O ATOM 1896 CB ASN A 646 −7.493 35.823 −41.891 1.00 79.53 C ATOM 1897 CG ASN A 646 −6.094 35.384 −42.271 1.00 82.65 C ATOM 1898 OD1 ASN A 646 −5.190 35.348 −41.430 1.00 76.66 O ATOM 1899 ND2 ASN A 646 −5.901 35.058 −43.545 1.00 83.32 N ATOM 1900 N SER A 647 −10.020 36.433 −39.887 1.00 76.98 N ATOM 1901 CA SER A 647 −11.118 37.346 −39.589 1.00 83.02 C ATOM 1902 C SER A 647 −11.333 37.525 −38.082 1.00 70.05 C ATOM 1903 O SER A 647 −12.094 38.390 −37.654 1.00 73.28 O ATOM 1904 CB SER A 647 −12.408 36.859 −40.255 1.00 85.08 C ATOM 1905 OG SER A 647 −13.404 37.866 −40.223 1.00 95.16 O ATOM 1906 N VAL A 648 −10.635 36.722 −37.288 1.00 53.98 N ATOM 1907 CA VAL A 648 −10.877 36.655 −35.845 1.00 49.93 C ATOM 1908 C VAL A 648 −10.020 37.660 −35.075 1.00 55.09 C ATOM 1909 O VAL A 648 −8.850 37.864 −35.386 1.00 58.76 O ATOM 1910 CB VAL A 648 −10.664 35.216 −35.342 1.00 54.96 C ATOM 1911 CG1 VAL A 648 −10.837 35.114 −33.814 1.00 49.88 C ATOM 1912 CG2 VAL A 648 −11.613 34.284 −36.093 1.00 52.35 C ATOM 1913 N SER A 649 −10.621 38.296 −34.077 1.00 54.72 N ATOM 1914 CA SER A 649 −9.959 39.371 −33.359 1.00 55.80 C ATOM 1915 C SER A 649 −8.798 38.856 −32.519 1.00 64.19 C ATOM 1916 O SER A 649 −8.737 37.681 −32.159 1.00 51.65 O ATOM 1917 CB SER A 649 −10.951 40.087 −32.452 1.00 59.53 C ATOM 1918 OG SER A 649 −11.251 39.279 −31.328 1.00 56.69 O ATOM 1919 N ASP A 650 −7.890 39.764 −32.188 1.00 65.03 N ATOM 1920 CA ASP A 650 −6.731 39.430 −31.384 1.00 62.27 C ATOM 1921 C ASP A 650 −7.115 39.123 −29.959 1.00 60.66 C ATOM 1922 O ASP A 650 −6.490 38.283 −29.306 1.00 63.51 O ATOM 1923 CB ASP A 650 −5.742 40.588 −31.416 1.00 73.44 C ATOM 1924 CG ASP A 650 −4.447 40.213 −32.070 1.00 71.61 C ATOM 1925 OD1 ASP A 650 −4.469 39.380 −32.994 1.00 65.73 O ATOM 1926 OD2 ASP A 650 −3.401 40.739 −31.645 1.00 74.01 O ATOM 1927 N THR A 651 −8.141 39.813 −29.470 1.00 57.25 N ATOM 1928 CA THR A 651 −8.639 39.583 −28.117 1.00 57.92 C ATOM 1929 C THR A 651 −9.103 38.139 −27.967 1.00 55.31 C ATOM 1930 O THR A 651 −8.844 37.493 −26.957 1.00 50.11 O ATOM 1931 CB THR A 651 −9.825 40.504 −27.792 1.00 67.54 C ATOM 1932 OG1 THR A 651 −9.547 41.829 −28.258 1.00 88.46 O ATOM 1933 CG2 THR A 651 −10.059 40.545 −26.309 1.00 71.04 C ATOM 1934 N ALA A 652 −9.793 37.643 −28.990 1.00 59.13 N ATOM 1935 CA ALA A 652 −10.317 36.282 −28.990 1.00 44.58 C ATOM 1936 C ALA A 652 −9.190 35.260 −28.987 1.00 45.16 C ATOM 1937 O ALA A 652 −9.224 34.282 −28.239 1.00 46.28 O ATOM 1938 CB ALA A 652 −11.187 36.064 −30.220 1.00 44.12 C ATOM 1939 N LYS A 653 −8.213 35.477 −29.861 1.00 47.31 N ATOM 1940 CA LYS A 653 −7.091 34.563 −29.981 1.00 45.21 C ATOM 1941 C LYS A 653 −6.345 34.513 −28.655 1.00 52.74 C ATOM 1942 O LYS A 653 −5.925 33.444 −28.205 1.00 46.73 O ATOM 1943 CB LYS A 653 −6.152 35.020 −31.086 1.00 44.75 C ATOM 1944 CG LYS A 653 −6.747 34.910 −32.507 1.00 47.33 C ATOM 1945 CD LYS A 653 −5.863 35.563 −33.535 1.00 52.41 C ATOM 1946 CE LYS A 653 −6.554 35.569 −34.890 1.00 55.94 C ATOM 1947 NZ LYS A 653 −5.672 36.072 −35.966 1.00 57.08 N ATOM 1948 N ASP A 654 −6.194 35.672 −28.025 1.00 52.11 N ATOM 1949 CA ASP A 654 −5.502 35.737 −26.735 1.00 56.74 C ATOM 1950 C ASP A 654 −6.198 34.892 −25.654 1.00 49.40 C ATOM 1951 O ASP A 654 −5.555 34.128 −24.937 1.00 50.64 O ATOM 1952 CB ASP A 654 −5.333 37.187 −26.285 1.00 59.68 C ATOM 1953 CG ASP A 654 −4.611 37.300 −24.960 1.00 64.87 C ATOM 1954 OD2 ASP A 654 −5.288 37.575 −23.952 1.00 56.40 O ATOM 1955 OD1 ASP A 654 −3.375 37.107 −24.924 1.00 51.70 O ATOM 1956 N LEU A 655 −7.517 35.013 −25.554 1.00 42.87 N ATOM 1957 CA LEU A 655 −8.280 34.247 −24.569 1.00 38.45 C ATOM 1958 C LEU A 655 −8.162 32.753 −24.855 1.00 43.67 C ATOM 1959 O LEU A 655 −7.944 31.951 −23.946 1.00 43.22 O ATOM 1960 CB LEU A 655 −9.759 34.643 −24.653 1.00 40.92 C ATOM 1961 CG LEU A 655 −10.701 34.528 −23.456 1.00 52.76 C ATOM 1962 CD1 LEU A 655 −12.026 33.992 −23.915 1.00 39.47 C ATOM 1963 CD2 LEU A 655 −10.153 33.750 −22.238 1.00 45.57 C ATOM 1964 N VAL A 656 −8.302 32.389 −26.128 1.00 39.89 N ATOM 1965 CA VAL A 656 −8.210 30.992 −26.528 1.00 39.92 C ATOM 1966 C VAL A 656 −6.862 30.405 −26.108 1.00 40.05 C ATOM 1967 O VAL A 656 −6.799 29.318 −25.536 1.00 44.62 O ATOM 1968 CB VAL A 656 −8.297 30.858 −28.053 1.00 38.60 C ATOM 1969 CG1 VAL A 656 −7.939 29.447 −28.467 1.00 45.48 C ATOM 1970 CG2 VAL A 656 −9.682 31.234 −28.532 1.00 47.83 C ATOM 1971 N SER A 657 −5.794 31.135 −26.398 1.00 44.40 N ATOM 1972 CA SER A 657 −4.449 30.659 −26.089 1.00 44.43 C ATOM 1973 C SER A 657 −4.273 30.406 −24.590 1.00 51.36 C ATOM 1974 O SER A 657 −3.559 29.487 −24.185 1.00 47.55 O ATOM 1975 CB SER A 657 −3.386 31.645 −26.589 1.00 51.43 C ATOM 1976 OG SER A 657 −3.424 32.875 −25.867 1.00 53.90 O ATOM 1977 N LYS A 658 −4.927 31.229 −23.779 1.00 43.89 N ATOM 1978 CA LYS A 658 −4.785 31.157 −22.324 1.00 44.74 C ATOM 1979 C LYS A 658 −5.714 30.117 −21.684 1.00 47.50 C ATOM 1980 O LYS A 658 −5.467 29.652 −20.567 1.00 45.05 O ATOM 1981 CB LYS A 658 −4.989 32.544 −21.711 1.00 41.89 C ATOM 1982 CG LYS A 658 −3.760 33.449 −21.864 1.00 46.92 C ATOM 1983 CD LYS A 658 −4.077 34.898 −21.513 1.00 51.15 C ATOM 1984 CE LYS A 658 −2.828 35.765 −21.594 1.00 59.87 C ATOM 1985 NZ LYS A 658 −3.213 37.201 −21.621 1.00 65.90 N ATOM 1986 N MET A 659 −6.760 29.744 −22.416 1.00 45.79 N ATOM 1987 CA MET A 659 −7.686 28.702 −21.988 1.00 38.20 C ATOM 1988 C MET A 659 −7.157 27.313 −22.337 1.00 49.92 C ATOM 1989 O MET A 659 −7.407 26.359 −21.604 1.00 42.62 O ATOM 1990 CB MET A 659 −9.072 28.933 −22.594 1.00 40.10 C ATOM 1991 CG MET A 659 −9.770 30.170 −22.046 1.00 44.81 C ATOM 1992 SD MET A 659 −11.463 30.356 −22.674 1.00 42.14 S ATOM 1993 CE MET A 659 −12.302 29.071 −21.747 1.00 35.38 C ATOM 1994 N LEU A 660 −6.411 27.212 −23.441 1.00 44.18 N ATOM 1995 CA LEU A 660 −5.856 25.935 −23.907 1.00 39.14 C ATOM 1996 C LEU A 660 −4.409 25.712 −23.497 1.00 43.52 C ATOM 1997 O LEU A 660 −3.798 24.723 −23.924 1.00 47.80 O ATOM 1998 CB LEU A 660 −5.928 25.841 −25.438 1.00 37.09 C ATOM 1999 CG LEU A 660 −7.337 25.742 −25.990 1.00 30.90 C ATOM 2000 CD2 LEU A 660 −7.996 24.515 −25.423 1.00 38.78 C ATOM 2001 CD1 LEU A 660 −7.278 25.677 −27.547 1.00 33.76 C ATOM 2002 N HIS A 661 −3.862 26.620 −22.686 1.00 44.90 N ATOM 2003 CA HIS A 661 −2.471 26.519 −22.242 1.00 47.68 C ATOM 2004 C HIS A 661 −2.240 25.111 −21.701 1.00 51.69 C ATOM 2005 O HIS A 661 −3.057 24.592 −20.945 1.00 46.85 O ATOM 2006 CB HIS A 661 −2.186 27.557 −21.152 1.00 52.93 C ATOM 2007 CG HIS A 661 −0.730 27.805 −20.917 1.00 57.37 C ATOM 2008 ND1 HIS A 661 0.161 26.796 −20.614 1.00 57.09 N ATOM 2009 CD2 HIS A 661 −0.009 28.951 −20.940 1.00 58.42 C ATOM 2010 CE1 HIS A 661 1.370 27.312 −20.464 1.00 57.67 C ATOM 2011 NE2 HIS A 661 1.293 28.616 −20.653 1.00 63.24 N ATOM 2012 N VAL A 662 −1.156 24.469 −22.110 1.00 47.58 N ATOM 2013 CA VAL A 662 −0.941 23.076 −21.729 1.00 55.82 C ATOM 2014 C VAL A 662 −0.617 22.923 −20.230 1.00 59.07 C ATOM 2015 O VAL A 662 −0.859 21.876 −19.630 1.00 62.39 O ATOM 2016 CB VAL A 662 0.164 22.424 −22.595 1.00 56.28 C ATOM 2017 CG1 VAL A 662 1.506 23.027 −22.279 1.00 56.12 C ATOM 2018 CG2 VAL A 662 0.185 20.924 −22.382 1.00 70.78 C ATOM 2019 N ASP A 663 −0.083 23.981 −19.630 1.00 50.65 N ATOM 2020 CA ASP A 663 0.267 23.972 −18.206 1.00 53.18 C ATOM 2021 C ASP A 663 −0.942 24.429 −17.386 1.00 55.66 C ATOM 2022 O ASP A 663 −1.325 25.599 −17.442 1.00 51.36 O ATOM 2023 CB ASP A 663 1.442 24.908 −17.958 1.00 53.93 C ATOM 2024 CG ASP A 663 2.021 24.780 −16.563 1.00 62.02 C ATOM 2025 OD1 ASP A 663 1.336 24.286 −15.640 1.00 63.51 O ATOM 2026 OD2 ASP A 663 3.175 25.189 −16.390 1.00 65.85 O ATOM 2027 N PRO A 664 −1.541 23.511 −16.614 1.00 54.83 N ATOM 2028 CA PRO A 664 −2.747 23.885 −15.864 1.00 59.58 C ATOM 2029 C PRO A 664 −2.474 24.986 −14.826 1.00 51.43 C ATOM 2030 O PRO A 664 −3.394 25.723 −14.479 1.00 62.68 O ATOM 2031 CB PRO A 664 −3.155 22.576 −15.183 1.00 57.35 C ATOM 2032 CG PRO A 664 −1.907 21.779 −15.108 1.00 58.47 C ATOM 2033 CD PRO A 664 −1.143 22.115 −16.358 1.00 59.05 C ATOM 2034 N HIS A 665 −1.229 25.110 −14.379 1.00 53.81 N ATOM 2035 CA HIS A 665 −0.856 26.172 −13.443 1.00 55.25 C ATOM 2036 C HIS A 665 −0.920 27.540 −14.113 1.00 67.94 C ATOM 2037 O HIS A 665 −1.169 28.543 −13.459 1.00 72.19 O ATOM 2038 CB HIS A 665 0.531 25.923 −12.839 1.00 68.20 C ATOM 2039 CG HIS A 665 0.633 24.623 −12.103 1.00 81.80 C ATOM 2040 ND1 HIS A 665 −0.048 24.379 −10.930 1.00 93.49 N ATOM 2041 CD2 HIS A 665 1.313 23.486 −12.387 1.00 85.72 C ATOM 2042 CE1 HIS A 665 0.217 23.153 −10.515 1.00 98.26 C ATOM 2043 NE2 HIS A 665 1.040 22.589 −11.383 1.00 96.37 N ATOM 2044 N GLN A 666 −0.729 27.575 −15.428 1.00 61.34 N ATOM 2045 CA GLN A 666 −0.765 28.841 −16.147 1.00 54.11 C ATOM 2046 C GLN A 666 −2.113 29.110 −16.813 1.00 57.16 C ATOM 2047 O GLN A 666 −2.440 30.254 −17.122 1.00 56.11 O ATOM 2048 CB GLN A 666 0.357 28.897 −17.183 1.00 63.23 C ATOM 2049 CG GLN A 666 1.752 28.854 −16.573 1.00 70.26 C ATOM 2050 CD GLN A 666 2.839 28.808 −17.635 1.00 84.33 C ATOM 2051 OE1 GLN A 666 3.005 29.749 −18.412 1.00 84.78 O ATOM 2052 NE2 GLN A 666 3.572 27.701 −17.684 1.00 84.31 N ATOM 2053 N ARG A 667 −2.884 28.054 −17.041 1.00 47.33 N ATOM 2054 CA ARG A 667 −4.185 28.166 −17.696 1.00 40.19 C ATOM 2055 C ARG A 667 −5.137 29.060 −16.900 1.00 48.64 C ATOM 2056 O ARG A 667 −5.136 29.016 −15.680 1.00 47.85 O ATOM 2057 CB ARG A 667 −4.793 26.767 −17.839 1.00 48.02 C ATOM 2058 CG ARG A 667 −6.095 26.702 −18.654 1.00 47.75 C ATOM 2059 CD ARG A 667 −6.497 25.239 −18.853 1.00 41.86 C ATOM 2060 NE ARG A 667 −5.341 24.442 −19.284 1.00 43.38 N ATOM 2061 CZ ARG A 667 −5.151 23.170 −18.954 1.00 46.56 C ATOM 2062 NH1 ARG A 667 −6.055 22.546 −18.216 1.00 48.07 N ATOM 2063 NH2 ARG A 667 −4.064 22.518 −19.363 1.00 44.69 N ATOM 2064 N LEU A 668 −5.973 29.847 −17.571 1.00 47.24 N ATOM 2065 CA LEU A 668 −6.899 30.700 −16.823 1.00 55.91 C ATOM 2066 C LEU A 668 −7.881 29.865 −16.001 1.00 53.76 C ATOM 2067 O LEU A 668 −8.220 28.744 −16.378 1.00 48.48 O ATOM 2068 CB LEU A 668 −7.680 31.625 −17.758 1.00 43.49 C ATOM 2069 CG LEU A 668 −6.901 32.617 −18.614 1.00 55.61 C ATOM 2070 CD1 LEU A 668 −7.872 33.404 −19.503 1.00 56.21 C ATOM 2071 CD2 LEU A 668 −6.041 33.548 −17.756 1.00 56.05 C ATOM 2072 N THR A 669 −8.316 30.409 −14.869 1.00 50.55 N ATOM 2073 CA THR A 669 −9.419 29.833 −14.111 1.00 41.19 C ATOM 2074 C THR A 669 −10.717 30.396 −14.693 1.00 43.84 C ATOM 2075 O THR A 669 −10.688 31.318 −15.501 1.00 49.00 O ATOM 2076 CB THR A 669 −9.346 30.253 −12.635 1.00 42.37 C ATOM 2077 OG1 THR A 669 −9.548 31.668 −12.549 1.00 54.85 O ATOM 2078 CG2 THR A 669 −7.985 29.880 −12.013 1.00 49.02 C ATOM 2079 N ALA A 670 −11.859 29.855 −14.290 1.00 49.96 N ATOM 2080 CA ALA A 670 −13.140 30.411 −14.742 1.00 46.87 C ATOM 2081 C ALA A 670 −13.286 31.883 −14.334 1.00 48.16 C ATOM 2082 O ALA A 670 −13.844 32.698 −15.076 1.00 41.97 O ATOM 2083 CB ALA A 670 −14.293 29.596 −14.181 1.00 45.72 C ATOM 2084 N ALA A 671 −12.791 32.216 −13.143 1.00 46.88 N ATOM 2085 CA ALA A 671 −12.832 33.585 −12.647 1.00 46.92 C ATOM 2086 C ALA A 671 −12.064 34.542 −13.553 1.00 53.00 C ATOM 2087 O ALA A 671 −12.542 35.632 −13.846 1.00 50.46 O ATOM 2088 CB ALA A 671 −12.289 33.653 −11.194 1.00 50.19 C ATOM 2089 N LEU A 672 −10.878 34.131 −14.005 1.00 43.14 N ATOM 2090 CA LEU A 672 −10.063 34.976 −14.868 1.00 54.99 C ATOM 2091 C LEU A 672 −10.615 35.053 −16.294 1.00 52.36 C ATOM 2092 O LEU A 672 −10.449 36.066 −16.979 1.00 49.83 O ATOM 2093 CB LEU A 672 −8.605 34.493 −14.880 1.00 54.82 C ATOM 2094 CG LEU A 672 −7.638 35.186 −13.913 1.00 62.76 C ATOM 2095 CD1 LEU A 672 −8.384 36.019 −12.883 1.00 63.63 C ATOM 2096 CD2 LEU A 672 −6.744 34.166 −13.233 1.00 61.37 C ATOM 2097 N VAL A 673 −11.266 33.987 −16.748 1.00 48.68 N ATOM 2098 CA VAL A 673 −11.885 34.030 −18.072 1.00 43.52 C ATOM 2099 C VAL A 673 −12.919 35.145 −18.068 1.00 42.63 C ATOM 2100 O VAL A 673 −13.029 35.910 −19.018 1.00 48.16 O ATOM 2101 CB VAL A 673 −12.586 32.707 −18.441 1.00 43.17 C ATOM 2102 CG1 VAL A 673 −13.478 32.894 −19.702 1.00 41.02 C ATOM 2103 CG2 VAL A 673 −11.559 31.613 −18.670 1.00 43.87 C ATOM 2104 N LEU A 674 −13.633 35.267 −16.958 1.00 47.18 N ATOM 2105 CA LEU A 674 −14.726 36.227 −16.887 1.00 49.17 C ATOM 2106 C LEU A 674 −14.240 37.679 −16.818 1.00 56.65 C ATOM 2107 O LEU A 674 −15.028 38.602 −17.035 1.00 54.70 O ATOM 2108 CB LEU A 674 −15.655 35.895 −15.720 1.00 55.45 C ATOM 2109 CG LEU A 674 −16.445 34.591 −15.880 1.00 47.01 C ATOM 2110 CD1 LEU A 674 −17.008 34.160 −14.552 1.00 46.57 C ATOM 2111 CD2 LEU A 674 −17.584 34.757 −16.910 1.00 45.02 C ATOM 2112 N ARG A 675 −12.952 37.889 −16.537 1.00 47.08 N ATOM 2113 CA ARG A 675 −12.413 39.254 −16.523 1.00 51.19 C ATOM 2114 C ARG A 675 −11.549 39.536 −17.748 1.00 52.92 C ATOM 2115 O ARG A 675 −10.895 40.571 −17.821 1.00 52.21 O ATOM 2116 CB ARG A 675 −11.621 39.564 −15.242 1.00 59.37 C ATOM 2117 CG ARG A 675 −11.916 38.677 −14.060 1.00 64.55 C ATOM 2118 CD ARG A 675 −13.322 38.849 −13.507 1.00 75.27 C ATOM 2119 NE ARG A 675 −13.744 37.639 −12.799 0.55 73.03 N ATOM 2120 CZ ARG A 675 −14.961 37.435 −12.305 0.49 75.82 C ATOM 2121 NH1 ARG A 675 −15.903 38.362 −12.428 0.78 83.63 N ATOM 2122 NH2 ARG A 675 −15.235 36.297 −11.685 0.59 72.11 N ATOM 2123 N HIS A 676 −11.542 38.617 −18.710 1.00 52.34 N ATOM 2124 CA HIS A 676 −10.830 38.853 −19.966 1.00 57.41 C ATOM 2125 C HIS A 676 −11.646 39.855 −20.783 1.00 46.57 C ATOM 2126 O HIS A 676 −12.878 39.792 −20.785 1.00 51.95 O ATOM 2127 CB HIS A 676 −10.651 37.538 −20.735 1.00 57.21 C ATOM 2128 CG HIS A 676 −9.639 37.605 −21.841 1.00 50.23 C ATOM 2129 ND1 HIS A 676 −9.939 38.081 −23.099 1.00 51.23 N ATOM 2130 CD2 HIS A 676 −8.335 37.240 −21.878 1.00 49.23 C ATOM 2131 CE1 HIS A 676 −8.861 38.013 −23.862 1.00 51.68 C ATOM 2132 NE2 HIS A 676 −7.875 37.501 −23.148 1.00 48.78 N ATOM 2133 N PRO A 677 −10.967 40.796 −21.456 1.00 51.37 N ATOM 2134 CA PRO A 677 −11.651 41.837 −22.232 1.00 59.74 C ATOM 2135 C PRO a 677 −12.593 41.291 −23.316 1.00 61.98 C ATOM 2136 O PRO A 677 −13.564 41.966 −23.660 1.00 57.68 O ATOM 2137 CB PRO A 677 −10.498 42.643 −22.851 1.00 65.29 C ATOM 2138 CG PRO A 677 −9.248 41.854 −22.581 1.00 66.58 C ATOM 2139 CD PRO A 677 −9.515 41.024 −21.377 1.00 56.29 C ATOM 2140 N TRP A 678 −12.319 40.093 −23.830 1.00 49.37 N ATOM 2141 CA TRP A 678 −13.188 39.477 −24.827 1.00 49.33 C ATOM 2142 C TRP A 678 −14.549 39.184 −24.203 1.00 46.95 C ATOM 2143 O TRP A 678 −15.573 39.242 −24.878 1.00 50.60 O ATOM 2144 CB TRP A 678 −12.565 38.189 −25.393 1.00 51.10 C ATOM 2145 CG TRP A 678 −13.241 37.712 −26.658 1.00 50.50 C ATOM 2146 CD1 TRP A 678 −13.133 38.262 −27.904 1.00 49.25 C ATOM 2147 CD2 TRP A 678 −14.121 36.589 −26.789 1.00 46.49 C ATOM 2148 NE1 TRP A 678 −13.901 37.555 −28.808 1.00 50.52 N ATOM 2149 CE2 TRP A 678 −14.513 36.520 −28.147 1.00 45.86 C ATOM 2150 CE3 TRP A 678 −14.618 35.635 −25.892 1.00 44.19 C ATOM 2151 CZ2 TRP A 678 −15.378 35.535 −28.629 1.00 41.37 C ATOM 2152 CZ3 TRP A 678 −15.472 34.659 −26.369 1.00 39.50 C ATOM 2153 CH2 TRP A 678 −15.843 34.617 −27.737 1.00 38.18 C ATOM 2154 N ILE A 679 −14.559 38.875 −22.908 1.00 47.39 N ATOM 2155 CA ILE A 679 −15.822 38.633 −22.221 1.00 50.01 C ATOM 2156 C ILE A 679 −16.446 39.933 −21.715 1.00 59.26 C ATOM 2157 O ILE A 679 −17.625 40.193 −21.966 1.00 58.60 O ATOM 2158 CB ILE A 679 −15.673 37.644 −21.049 1.00 48.59 C ATOM 2159 CG1 ILE A 679 −15.306 36.246 −21.571 1.00 43.63 C ATOM 2160 CG2 ILE A 679 −16.955 37.613 −20.215 1.00 53.80 C ATOM 2161 CD1 ILE A 679 −16.434 35.493 −22.258 1.00 42.91 C ATOM 2162 N VAL A 680 −15.672 40.758 −21.013 1.00 57.00 N ATOM 2163 CA VAL A 680 −16.265 41.964 −20.422 1.00 65.55 C ATOM 2164 C VAL A 680 −16.593 43.054 −21.446 1.00 62.55 C ATOM 2165 O VAL A 680 −17.602 43.739 −21.306 1.00 62.99 O ATOM 2166 CB VAL A 680 −15.469 42.551 −19.193 1.00 63.88 C ATOM 2167 CG2 VAL A 680 −14.741 43.836 −19.555 1.00 69.05 C ATOM 2168 CG1 VAL A 680 −14.514 41.532 −18.603 1.00 57.19 C ATOM 2169 N HIS A 681 −15.762 43.210 −22.475 1.00 59.59 N ATOM 2170 CA HIS A 681 −16.032 44.225 −23.493 1.00 65.61 C ATOM 2171 C HIS A 681 −16.571 43.605 −24.767 1.00 68.83 C ATOM 2172 O HIS A 681 −16.104 43.906 −25.868 1.00 66.24 O ATOM 2173 CB HIS A 681 −14.789 45.065 −23.781 1.00 69.47 C ATOM 2174 CG HIS A 681 −14.379 45.934 −22.634 1.00 75.31 C ATOM 2175 ND1 HIS A 681 −13.214 45.732 −21.925 1.00 77.96 N ATOM 2176 CD2 HIS A 681 −14.992 46.995 −22.057 1.00 76.75 C ATOM 2177 CE1 HIS A 681 −13.120 46.640 −20.969 1.00 80.37 C ATOM 2178 NE2 HIS A 681 −14.186 47.418 −21.027 1.00 82.13 N ATOM 2179 N TRP A 682 −17.562 42.736 −24.598 1.00 71.01 N ATOM 2180 CA TRP A 682 −18.200 42.052 −25.712 1.00 72.61 C ATOM 2181 C TRP A 682 −18.759 43.045 −26.729 1.00 74.21 C ATOM 2182 O TRP A 682 −18.725 42.790 −27.931 1.00 60.27 O ATOM 2183 CB TRP A 682 −19.320 41.145 −25.194 1.00 72.71 C ATOM 2184 CG TRP A 682 −20.286 41.873 −24.320 1.00 80.28 C ATOM 2185 CD1 TRP A 682 −20.185 42.065 −22.974 1.00 78.92 C ATOM 2186 CD2 TRP A 682 −21.495 42.527 −24.731 1.00 87.73 C ATOM 2187 NE1 TRP A 682 −21.259 42.794 −22.518 1.00 86.91 N ATOM 2188 CE2 TRP A 682 −22.077 43.091 −23.577 1.00 91.60 C ATOM 2189 CE3 TRP A 682 −22.142 42.689 −25.960 1.00 86.59 C ATOM 2190 CZ2 TRP A 682 −23.275 43.802 −23.616 1.00 94.47 C ATOM 2191 CZ3 TRP A 682 −23.333 43.397 −25.997 1.00 90.03 C ATOM 2192 CH2 TRP A 682 −23.885 43.943 −24.833 1.00 94.42 C ATOM 2193 N ASP A 683 −19.246 44.186 −26.245 1.00 83.47 N ATOM 2194 CA ASP A 683 −19.921 45.159 −27.105 1.00 87.33 C ATOM 2195 C ASP A 683 −18.992 45.884 −28.076 1.00 85.58 C ATOM 2196 O ASP A 683 −19.428 46.767 −28.809 1.00 92.15 O ATOM 2197 CB ASP A 683 −20.719 46.173 −26.274 1.00 97.20 C ATOM 2198 CG ASP A 683 −19.848 46.967 −25.318 1.00 98.57 C ATOM 2199 OD1 ASP A 683 −19.209 47.942 −25.765 1.00 96.90 O ATOM 2200 OD2 ASP A 683 −19.813 46.622 −24.116 1.00 101.60 O ATOM 2201 N GLN A 684 −17.717 45.509 −28.080 1.00 83.20 N ATOM 2202 CA GLN A 684 −16.762 46.061 −29.033 1.00 82.42 C ATOM 2203 C GLN A 684 −16.307 45.002 −30.028 1.00 82.55 C ATOM 2204 O GLN A 684 −15.550 45.284 −30.956 1.00 76.88 O ATOM 2205 CB GLN A 684 −15.560 46.643 −28.302 1.00 81.31 C ATOM 2206 CG GLN A 684 −15.943 47.708 −27.311 1.00 88.27 C ATOM 2207 CD GLN A 684 −14.809 48.652 −27.033 1.00 96.97 C ATOM 2208 OE1 GLN A 684 −13.844 48.297 −26.357 1.00 100.26 O ATOM 2209 NE2 GLN A 684 −14.904 49.864 −27.569 1.00 104.02 N ATOM 2210 N LEU A 685 −16.779 43.780 −29.822 1.00 74.58 N ATOM 2211 CA LEU A 685 −16.458 42.675 −30.709 1.00 69.60 C ATOM 2212 C LEU A 685 −17.117 42.849 −32.075 1.00 71.19 C ATOM 2213 O LEU A 685 −18.215 43.394 −32.179 1.00 74.92 O ATOM 2214 CB LEU A 685 −16.902 41.352 −30.081 1.00 65.22 C ATOM 2215 CG LEU A 685 −15.896 40.585 −29.215 1.00 66.91 C ATOM 2216 CD1 LEU A 685 −14.894 41.500 −28.532 1.00 63.39 C ATOM 2217 CD2 LEU A 685 −16.641 39.756 −28.186 1.00 60.15 C ATOM 2218 N PRO A 686 −16.439 42.387 −33.129 1.00 65.37 N ATOM 2219 CA PRO A 686 −17.017 42.403 −34.478 1.00 74.70 C ATOM 2220 C PRO A 686 −18.329 41.621 −34.529 1.00 77.05 C ATOM 2221 O PRO A 686 −18.463 40.568 −33.892 1.00 64.79 O ATOM 2222 CB PRO A 686 −15.945 41.717 −35.334 1.00 76.95 C ATOM 2223 CG PRO A 686 −14.993 41.071 −34.359 1.00 77.08 C ATOM 2224 CD PRO A 686 −15.058 41.881 −33.114 1.00 63.78 C ATOM 2225 N GLN A 687 −19.299 42.144 −35.266 1.00 81.56 N ATOM 2226 CA GLN A 687 −20.589 41.482 −35.364 1.00 83.98 C ATOM 2227 C GLN A 687 −20.827 40.931 −36.761 1.00 83.77 C ATOM 2228 O GLN A 687 −21.890 40.372 −37.043 1.00 78.95 O ATOM 2229 CB GLN A 687 −21.716 42.425 −34.952 1.00 85.08 C ATOM 2230 CG GLN A 687 −21.761 43.718 −35.731 1.00 88.67 C ATOM 2231 CD GLN A 687 −22.860 44.626 −35.231 1.00 101.14 C ATOM 2232 OE1 GLN A 687 −23.276 44.527 −34.076 1.00 103.37 O ATOM 2233 NE2 GLN A 687 −23.351 45.505 −36.099 1.00 106.49 N ATOM 2234 N TYR A 688 −19.839 41.085 −37.637 1.00 91.08 N ATOM 2235 CA TYR A 688 −19.916 40.425 −38.934 1.00 93.40 C ATOM 2236 C TYR A 688 −19.684 38.930 −38.763 1.00 79.26 C ATOM 2237 O TYR A 688 −19.143 38.480 −37.737 1.00 67.66 O ATOM 2238 CB TYR A 688 −18.965 41.033 −39.975 1.00 107.92 C ATOM 2239 CG TYR A 688 −17.581 41.405 −39.489 1.00 111.64 C ATOM 2240 CD2 TYR A 688 −16.537 40.484 −39.511 1.00 107.11 C ATOM 2241 CD1 TYR A 688 −17.309 42.693 −39.044 1.00 114.52 C ATOM 2242 CE2 TYR A 688 −15.267 40.835 −39.082 1.00 106.69 C ATOM 2243 CE1 TYR A 688 −16.045 43.051 −38.615 1.00 111.32 C ATOM 2244 CZ TYR A 688 −15.030 42.119 −38.636 1.00 109.36 C ATOM 2245 OH TYR A 688 −13.773 42.477 −38.207 1.00 110.11 O ATOM 2246 N GLN A 689 −20.112 38.163 −39.757 1.00 73.77 N ATOM 2247 CA GLN A 689 −20.100 36.716 −39.637 1.00 79.23 C ATOM 2248 C GLN A 689 −18.671 36.195 −39.534 1.00 74.30 C ATOM 2249 O GLN A 689 −17.738 36.761 −40.108 1.00 74.48 O ATOM 2250 CB GLN A 689 −20.854 36.065 −40.805 1.00 79.78 C ATOM 2251 CG GLN A 689 −20.135 36.124 −42.122 1.00 77.67 C ATOM 2252 CD GLN A 689 −20.971 35.572 −43.270 1.00 92.82 C ATOM 2253 OE1 GLN A 689 −21.862 34.746 −43.068 1.00 98.94 O ATOM 2254 NE2 GLN A 689 −20.691 36.036 −44.479 1.00 87.48 N ATOM 2255 N LEU A 690 −18.501 35.135 −38.760 1.00 70.97 N ATOM 2256 CA LEU A 690 −17.220 34.469 −38.697 1.00 66.42 C ATOM 2257 C LEU A 690 −17.010 33.707 −39.997 1.00 66.87 C ATOM 2258 O LEU A 690 −17.971 33.287 −40.644 1.00 70.72 O ATOM 2259 CB LEU A 690 −17.183 33.532 −37.493 1.00 52.53 C ATOM 2260 CG LEU A 690 −17.039 34.279 −36.170 1.00 52.75 C ATOM 2261 CD1 LEU A 690 −17.606 33.454 −35.038 1.00 47.15 C ATOM 2262 CD2 LEU A 690 −15.578 34.604 −35.921 1.00 55.33 C ATOM 2263 N ASN A 691 −15.757 33.555 −40.401 1.00 62.78 N ATOM 2264 CA ASN A 691 −15.450 32.746 −41.574 1.00 66.14 C ATOM 2265 C ASN A 691 −14.975 31.390 −41.081 1.00 60.68 C ATOM 2266 O ASN A 691 −13.886 31.268 −40.530 1.00 57.19 O ATOM 2267 CB ASN A 691 −14.379 33.418 −42.426 1.00 70.58 C ATOM 2268 CG ASN A 691 −14.138 32.694 −43.738 1.00 76.01 C ATOM 2269 OD1 ASN A 691 −15.078 32.317 −44.442 1.00 76.86 O ATOM 2270 ND2 ASN A 691 −12.868 32.485 −44.068 1.00 79.59 N ATOM 2271 N ARG A 692 −15.801 30.369 −41.250 1.00 56.68 N ATOM 2272 CA ARG A 692 −15.528 29.093 −40.611 1.00 59.75 C ATOM 2273 C ARG A 692 −15.632 27.926 −41.566 1.00 48.83 C ATOM 2274 O ARG A 692 −16.299 28.013 −42.590 1.00 52.06 O ATOM 2275 CB ARG A 692 −16.506 28.880 −39.450 1.00 49.16 C ATOM 2276 CG ARG A 692 −16.454 29.998 −38.413 1.00 46.46 C ATOM 2277 CD ARG A 692 −17.401 29.766 −37.242 1.00 40.65 C ATOM 2278 NE ARG A 692 −18.799 29.688 −37.673 1.00 42.47 N ATOM 2279 CZ ARG A 692 −19.796 29.295 −36.892 1.00 47.28 C ATOM 2280 NH1 ARG A 692 −19.551 28.949 −35.621 1.00 45.32 N ATOM 2281 NH2 ARG A 692 −21.026 29.252 −37.369 1.00 43.58 N ATOM 2282 N GLN A 693 −14.986 26.820 −41.212 1.00 50.21 N ATOM 2283 CA GLN A 693 −15.235 25.578 −41.916 1.00 56.23 C ATOM 2284 C GLN A 693 −16.710 25.247 −41.709 1.00 54.07 C ATOM 2285 O GLN A 693 −17.266 25.494 −40.636 1.00 60.31 O ATOM 2286 CB GLN A 693 −14.372 24.451 −41.354 1.00 47.88 C ATOM 2287 CG GLN A 693 −14.459 23.161 −42.164 1.00 59.77 C ATOM 2288 CD GLN A 693 −13.816 21.972 −41.458 1.00 63.23 C ATOM 2289 OE1 GLN A 693 −13.894 21.830 −40.226 1.00 59.28 O ATOM 2290 NE2 GLN A 693 −13.189 21.104 −42.240 1.00 58.73 N ATOM 2291 N ASP A 694 −17.352 24.710 −42.728 1.00 50.88 N ATOM 2292 CA ASP A 694 −18.714 24.238 −42.542 1.00 63.17 C ATOM 2293 C ASP A 694 −18.729 22.725 −42.647 1.00 53.78 C ATOM 2294 O ASP A 694 −19.055 22.187 −43.676 1.00 54.33 O ATOM 2295 CB ASP A 694 −19.655 24.854 −43.576 1.00 63.70 C ATOM 2296 CG ASP A 694 −21.082 24.305 −43.480 1.00 77.85 C ATOM 2297 OD1 ASP A 694 −21.504 23.904 −42.373 1.00 78.38 O ATOM 2298 OD2 ASP A 694 −21.782 24.274 −44.519 1.00 85.75 O ATOM 2299 N ALA A 695 −18.336 22.037 −41.580 1.00 57.64 N ATOM 2300 CA ALA A 695 −18.420 20.576 −41.585 1.00 52.13 C ATOM 2301 C ALA A 695 −18.775 20.101 −40.187 1.00 55.53 C ATOM 2302 O ALA A 695 −17.937 19.513 −39.499 1.00 48.32 O ATOM 2303 CB ALA A 695 −17.102 19.950 −42.056 1.00 57.90 C ATOM 2304 N PRO A 696 −20.018 20.377 −39.754 1.00 46.52 N ATOM 2305 CA PRO A 696 −20.417 20.092 −38.368 1.00 49.65 C ATOM 2306 C PRO A 696 −20.313 18.600 −38.047 1.00 50.37 C ATOM 2307 O PRO A 696 −19.947 18.249 −36.925 1.00 48.19 O ATOM 2308 CB PRO A 696 −21.887 20.559 −38.322 1.00 43.86 C ATOM 2309 CG PRO A 696 −22.339 20.512 −39.775 1.00 48.27 C ATOM 2310 CD PRO A 696 −21.125 20.951 −40.541 1.00 55.36 C ATOM 2311 N HIS A 697 −20.621 17.737 −39.011 1.00 45.13 N ATOM 2312 CA HIS A 697 −20.530 16.305 −38.762 1.00 46.88 C ATOM 2313 C HIS A 697 −19.079 15.835 −38.635 1.00 48.11 C ATOM 2314 O HIS A 697 −18.784 14.959 −37.827 1.00 48.57 O ATOM 2315 CB HIS A 697 −21.223 15.491 −39.839 1.00 52.98 C ATOM 2316 CG HIS A 697 −21.254 14.027 −39.543 1.00 54.49 C ATOM 2317 ND1 HIS A 697 −22.011 13.490 −38.522 1.00 54.53 N ATOM 2318 CD2 HIS A 697 −20.601 12.988 −40.117 1.00 52.96 C ATOM 2319 CE1 HIS A 697 −21.830 12.180 −38.489 1.00 56.64 C ATOM 2320 NE2 HIS A 697 −20.982 11.851 −39.448 1.00 52.41 N ATOM 2321 N LEU A 698 −18.183 16.403 −39.434 1.00 48.37 N ATOM 2322 CA LEU A 698 −16.750 16.113 −39.277 1.00 47.22 C ATOM 2323 C LEU A 698 −16.260 16.503 −37.879 1.00 43.55 C ATOM 2324 O LEU A 698 −15.517 15.761 −37.229 1.00 42.17 O ATOM 2325 CB LEU A 698 −15.944 16.877 −40.318 1.00 53.59 C ATOM 2326 CG LEU A 698 −14.492 16.436 −40.501 1.00 56.43 C ATOM 2327 CD1 LEU A 698 −14.442 14.992 −40.966 1.00 59.45 C ATOM 2328 CD2 LEU A 698 −13.816 17.326 −41.523 1.00 60.63 C ATOM 2329 N VAL A 699 −16.653 17.695 −37.442 1.00 42.57 N ATOM 2330 CA VAL A 699 −16.301 18.194 −36.114 1.00 41.25 C ATOM 2331 C VAL A 699 −16.811 17.265 −35.014 1.00 42.67 C ATOM 2332 O VAL A 699 −16.134 17.016 −34.016 1.00 39.23 O ATOM 2333 CB VAL A 699 −16.867 19.618 −35.873 1.00 45.97 C ATOM 2334 CG1 VAL A 699 −16.806 19.988 −34.383 1.00 45.19 C ATOM 2335 CG2 VAL A 699 −16.106 20.639 −36.702 1.00 44.68 C ATOM 2336 N LYS A 700 −18.024 16.765 −35.179 1.00 41.11 N ATOM 2337 CA LYS A 700 −18.587 15.896 −34.160 1.00 37.52 C ATOM 2338 C LYS A 700 −17.716 14.650 −34.033 1.00 50.22 C ATOM 2339 O LYS A 700 −17.480 14.158 −32.930 1.00 44.41 O ATOM 2340 CB LYS A 700 −20.037 15.546 −34.507 1.00 39.31 C ATOM 2341 CG LYS A 700 −20.680 14.502 −33.620 1.00 50.27 C ATOM 2342 CD LYS A 700 −22.162 14.304 −34.025 1.00 56.34 C ATOM 2343 CE LYS A 700 −22.874 13.297 −33.141 1.00 72.50 C ATOM 2344 NZ LYS A 700 −24.303 13.110 −33.568 1.00 83.14 N ATOM 2345 N GLY A 701 −17.212 14.161 −35.162 1.00 41.48 N ATOM 2346 CA GLY A 701 −16.330 13.011 −35.143 1.00 49.62 C ATOM 2347 C GLY A 701 −14.963 13.349 −34.555 1.00 47.68 C ATOM 2348 O GLY A 701 −14.369 12.541 −33.837 1.00 43.98 O ATOM 2349 N ALA A 702 −14.461 14.540 −34.866 1.00 43.33 N ATOM 2350 CA ALA A 702 −13.153 14.955 −34.361 1.00 43.89 C ATOM 2351 C ALA A 702 −13.213 15.151 −32.850 1.00 43.46 C ATOM 2352 O ALA A 702 −12.260 14.857 −32.138 1.00 43.27 O ATOM 2353 CB ALA A 702 −12.689 16.238 −35.041 1.00 38.33 C ATOM 2354 N MET A 703 −14.333 15.670 −32.373 1.00 36.37 N ATOM 2355 CA MET A 703 −14.534 15.900 −30.938 1.00 39.77 C ATOM 2356 C MET A 703 −14.583 14.550 −30.196 1.00 43.31 C ATOM 2357 O MET A 703 −13.898 14.358 −29.194 1.00 43.02 O ATOM 2358 CB MET A 703 −15.844 16.690 −30.721 1.00 44.38 C ATOM 2359 CG MET A 703 −15.849 17.573 −29.490 1.00 53.92 C ATOM 2360 SD MET A 703 −14.584 18.863 −29.530 1.00 42.25 S ATOM 2361 CE MET A 703 −15.423 20.170 −30.423 1.00 45.73 C ATOM 2362 N ALA A 704 −15.403 13.620 −30.696 1.00 44.48 N ATOM 2363 CA ALA A 704 −15.441 12.255 −30.164 1.00 44.67 C ATOM 2364 C ALA A 704 −14.036 11.631 −30.088 1.00 48.00 C ATOM 2365 O ALA A 704 −13.663 11.045 −29.067 1.00 41.38 O ATOM 2366 CB ALA A 704 −16.359 11.377 −31.007 1.00 45.29 C ATOM 2367 N ALA A 705 −13.268 11.757 −31.168 1.00 45.63 N ATOM 2368 CA ALA A 705 −11.902 11.229 −31.196 1.00 44.28 C ATOM 2369 C ALA A 705 −11.016 11.892 −30.135 1.00 43.64 C ATOM 2370 O ALA A 705 −10.166 11.247 −29.500 1.00 43.42 O ATOM 2371 CB ALA A 705 −11.281 11.421 −32.589 1.00 45.67 C ATOM 2372 N THR A 706 −11.198 13.193 −29.962 1.00 38.93 N ATOM 2373 CA THR A 706 −10.394 13.949 −29.014 1.00 42.52 C ATOM 2374 C THR A 706 −10.657 13.479 −27.572 1.00 41.02 C ATOM 2375 O THR A 706 −9.728 13.260 −26.792 1.00 39.98 O ATOM 2376 CB THR A 706 −10.705 15.453 −29.100 1.00 40.12 C ATOM 2377 OG1 THR A 706 −10.236 15.965 −30.355 1.00 38.36 O ATOM 2378 CG2 THR A 706 −9.991 16.200 −27.968 1.00 45.07 C ATOM 2379 N TYR A 707 −11.930 13.306 −27.233 1.00 38.07 N ATOM 2380 CA TYR A 707 −12.281 12.919 −25.868 1.00 38.98 C ATOM 2381 C TYR A 707 −12.061 11.442 −25.591 1.00 53.44 C ATOM 2382 O TYR A 707 −11.775 11.052 −24.459 1.00 46.93 O ATOM 2383 CB TYR A 707 −13.691 13.400 −25.487 1.00 38.72 C ATOM 2384 CG TYR A 707 −13.664 14.882 −25.209 1.00 38.67 C ATOM 2385 CD1 TYR A 707 −13.263 15.361 −23.963 1.00 44.25 C ATOM 2386 CD2 TYR A 707 −13.961 15.806 −26.212 1.00 39.38 C ATOM 2387 CE1 TYR A 707 −13.196 16.721 −23.707 1.00 41.35 C ATOM 2388 CE2 TYR A 707 −13.903 17.179 −25.966 1.00 39.98 C ATOM 2389 CZ TYR A 707 −13.515 17.624 −24.705 1.00 46.61 C ATOM 2390 OH TYR A 707 −13.441 18.970 −24.441 1.00 44.20 O ATOM 2391 N SER A 708 −12.168 10.627 −26.631 1.00 43.35 N ATOM 2392 CA SER A 708 −11.809 9.223 −26.515 1.00 46.79 C ATOM 2393 C SER A 708 −10.328 9.088 −26.171 1.00 52.37 C ATOM 2394 O SER A 708 −9.938 8.263 −25.333 1.00 52.51 O ATOM 2395 CB SER A 708 −12.092 8.491 −27.820 1.00 47.88 C ATOM 2396 OG SER A 708 −11.710 7.136 −27.708 1.00 55.30 O ATOM 2397 N ALA A 709 −9.503 9.896 −26.829 1.00 47.45 N ATOM 2398 CA ALA A 709 −8.065 9.845 −26.598 1.00 51.97 C ATOM 2399 C ALA A 709 −7.764 10.282 −25.162 1.00 54.76 C ATOM 2400 O ALA A 709 −6.956 9.662 −24.478 1.00 60.45 O ATOM 2401 CB ALA A 709 −7.321 10.722 −27.609 1.00 47.60 C ATOM 2402 N LEU A 710 −8.434 11.339 −24.718 1.00 56.74 N ATOM 2403 CA LEU A 710 −8.270 11.878 −23.366 1.00 64.72 C ATOM 2404 C LEU A 710 −8.610 10.895 −22.243 1.00 76.00 C ATOM 2405 O LEU A 710 −7.797 10.658 −21.348 1.00 77.82 O ATOM 2406 CB LEU A 710 −9.112 13.134 −23.206 1.00 57.59 C ATOM 2407 CG LEU A 710 −8.593 14.345 −23.967 1.00 61.96 C ATOM 2408 CD1 LEU A 710 −9.561 15.486 −23.808 1.00 61.59 C ATOM 2409 CD2 LEU A 710 −7.222 14.726 −23.457 1.00 63.32 C ATOM 2410 N ASN A 711 −9.809 10.325 −22.284 1.00 76.30 N ATOM 2411 CA ASN A 711 −10.221 9.357 −21.268 1.00 82.11 C ATOM 2412 C ASN A 711 −9.406 8.064 −21.358 1.00 85.04 C ATOM 2413 O ASN A 711 −9.437 7.229 −20.457 1.00 96.57 O ATOM 2414 CB ASN A 711 −11.721 9.073 −21.382 1.00 86.23 C ATOM 2415 CG ASN A 711 −12.547 10.344 −21.558 1.00 85.56 C ATOM 2416 OD1 ASN A 711 −12.104 11.442 −21.215 1.00 79.16 O ATOM 2417 ND2 ASN A 711 −13.752 10.197 −22.100 1.00 90.49 N ATOM 2418 N ARG A 712 −8.674 7.929 −22.459 1.00 80.63 N ATOM 2419 CA ARG A 712 −7.774 6.810 −22.710 1.00 88.96 C ATOM 2420 C ARG A 712 −8.471 5.452 −22.639 1.00 105.31 C ATOM 2421 O ARG A 712 −8.541 4.829 −21.580 1.00 116.64 O ATOM 2422 CB ARG A 712 −6.574 6.857 −21.762 1.00 90.39 C ATOM 2423 CG ARG A 712 −5.254 6.573 −22.447 1.00 96.35 C ATOM 2424 CD ARG A 712 −4.803 7.740 −23.311 1.00 97.25 C ATOM 2425 NE ARG A 712 −3.768 8.538 −22.656 1.00 98.51 N ATOM 2426 CZ ARG A 712 −3.974 9.724 −22.090 1.00 86.82 C ATOM 2427 NH1 ARG A 712 −5.184 10.268 −22.102 1.00 78.33 N ATOM 2428 NH2 ARG A 712 −2.964 10.367 −21.515 1.00 76.84 N TER HETATM 2429 NA NA B 1 −31.488 24.535 −13.655 1.00 39.63 NA TER HETATM 2430 O HOH C 1 −32.636 25.820 −15.386 1.00 40.55 O HETATM 2431 O HOH C 2 −26.467 14.643 −14.746 1.00 51.27 O HETATM 2432 O HOH C 3 −19.767 14.943 −14.926 1.00 44.57 O HETATM 2433 O HOH C 5 −21.928 18.736 −29.891 1.00 55.29 O HETATM 2434 O HOH C 6 −21.977 21.032 −28.134 1.00 54.67 O HETATM 2435 O HOH C 7 −27.024 31.068 −27.661 1.00 56.54 O HETATM 2436 O HOH C 8 −17.662 23.130 −38.884 1.00 41.46 O HETATM 2437 O HOH C 11 −14.203 18.516 −17.953 1.00 46.09 O HETATM 2438 O HOH C 12 −18.349 16.392 −27.389 1.00 49.93 O HETATM 2439 O HOH C 14 −28.723 32.234 −18.348 1.00 53.25 O HETATM 2440 O HOH C 15 −26.956 32.248 −38.301 1.00 59.35 O HETATM 2441 O HOH C 16 −20.720 12.766 −10.061 1.00 55.94 O HETATM 2442 O HOH C 17 −9.647 18.691 −30.771 1.00 42.06 O HETATM 2443 O HOH C 18 −4.993 19.226 −35.870 1.00 64.44 O HETATM 2444 O HOH C 19 −4.979 23.550 −34.509 1.00 49.96 O HETATM 2445 O HOH C 20 −11.079 11.645 −39.981 1.00 65.65 O HETATM 2446 O HOH C 21 −9.097 8.971 −30.113 1.00 51.44 O HETATM 2447 O HOH C 23 −11.894 27.746 −12.255 1.00 41.17 O HETATM 2448 O HOH C 24 −19.401 38.292 −22.877 1.00 44.74 O HETATM 2449 O HOH C 25 −20.395 17.757 −41.859 1.00 50.55 O HETATM 2450 O HOH C 26 −23.910 14.925 −37.256 1.00 57.58 O HETATM 2451 O HOH C 27 −18.823 14.617 −30.578 1.00 45.53 O HETATM 2452 O HOH C 28 −38.818 18.785 −19.917 1.00 50.45 O HETATM 2453 O HOH C 29 −32.416 15.673 −22.286 1.00 58.96 O HETATM 2454 O HOH C 30 −32.355 18.247 −28.169 1.00 57.23 O HETATM 2455 O HOH C 31 −20.446 18.396 −32.356 1.00 55.83 O HETATM 2456 O HOH C 32 −19.578 17.127 −30.036 1.00 52.70 O HETATM 2457 O HOH C 33 −17.570 14.311 −27.991 1.00 48.55 O HETATM 2458 O HOH C 34 −23.389 17.282 −36.853 1.00 50.44 O HETATM 2459 O HOH C 35 −25.031 31.785 −16.358 1.00 55.02 O HETATM 2460 O HOH C 36 −9.594 26.313 −12.794 1.00 47.26 O HETATM 2461 O HOH C 37 −7.739 26.687 −14.929 1.00 48.92 O HETATM 2462 O HOH C 38 −12.583 30.135 −10.948 1.00 49.79 O HETATM 2463 O HOH C 39 −13.577 17.248 −19.943 1.00 53.44 O HETATM 2464 O HOH C 40 −18.751 20.391 −2.679 1.00 61.13 O HETATM 2465 O HOH C 41 −21.946 15.441 −3.885 1.00 58.51 O HETATM 2466 O HOH C 42 −11.866 19.681 −36.557 1.00 44.87 O HETATM 2467 O HOH C 43 −17.480 12.603 −38.174 1.00 47.32 O HETATM 2468 O HOH C 44 −8.876 12.675 −40.019 1.00 63.50 O HETATM 2469 O HOH C 45 −17.253 38.072 −35.996 1.00 65.87 O HETATM 2470 O HOH C 46 −21.247 19.449 −34.579 1.00 55.33 O HETATM 2471 O HOH C 48 −22.870 9.738 −16.223 1.00 72.56 O HETATM 2472 O HOH C 51 −49.842 19.919 −18.763 1.00 60.38 O HETATM 2473 O HOH C 52 −43.587 19.075 −22.180 1.00 64.83 O HETATM 2474 O HOH C 53 −17.308 14.190 −2.774 1.00 59.16 O HETATM 2475 O HOH C 54 −35.681 26.001 −12.054 1.00 67.34 O HETATM 2476 O HOH C 55 −26.972 34.204 −19.854 1.00 64.53 O HETATM 2477 O HOH C 56 −19.188 25.775 −38.874 1.00 48.60 O HETATM 2478 O HOH C 57 −21.244 26.964 −41.091 1.00 88.31 O HETATM 2479 O HOH C 58 −28.278 26.066 −36.583 1.00 51.80 O HETATM 2480 O HOH C 60 −14.487 37.972 −36.305 1.00 59.45 O HETATM 2481 O HOH C 61 −13.392 32.614 −38.250 1.00 63.91 O HETATM 2482 O HOH C 62 −22.124 38.745 −22.968 1.00 61.38 O HETATM 2483 O HOH C 63 −23.296 31.666 −12.070 1.00 63.18 O HETATM 2484 O HOH C 65 −14.717 29.989 −9.096 1.00 50.67 O HETATM 2485 O HOH C 66 −11.620 16.033 −7.873 1.00 59.76 O HETATM 2486 O HOH C 68 −38.192 20.735 −22.286 1.00 60.14 O HETATM 2487 O HOH C 69 −11.945 19.550 −39.318 1.00 47.67 O HETATM 2488 O HOH C 70 −2.996 20.835 −33.270 1.00 58.09 O HETATM 2489 O HOH C 71 −7.135 20.747 −36.193 1.00 54.72 O HETATM 2490 O HOH C 73 −0.997 29.188 −24.899 1.00 62.24 O HETATM 2491 O HOH C 74 −3.914 43.077 −30.195 1.00 57.15 O HETATM 2492 O HOH C 75 −5.344 27.127 −13.672 1.00 50.75 O HETATM 2493 O HOH C 76 −7.783 24.771 −11.206 1.00 51.65 O HETATM 2494 O HOH C 77 −23.854 22.679 −42.214 1.00 58.39 O HETATM 2495 O HOH C 78 −16.649 12.176 −40.600 1.00 53.20 O HETATM 2496 O HOH C 80 −9.654 8.030 −32.912 1.00 68.94 O HETATM 2497 O HOH C 81 −15.431 10.244 −27.128 1.00 47.83 O HETATM 2498 O HOH C 84 −13.596 23.230 −6.760 1.00 58.68 O HETATM 2499 O HOH C 85 −11.286 24.450 −7.321 1.00 74.31 O HETATM 2500 O HOH C 86 −9.137 6.881 −28.733 1.00 57.50 O HETATM 2501 O HOH C 87 1.326 10.634 −28.584 1.00 70.53 O HETATM 2502 O HOH C 88 −9.015 42.504 −30.755 1.00 60.43 O HETATM 2503 O HOH C 89 −17.667 39.129 −16.837 1.00 61.70 O HETATM 2504 O HOH C 90 −34.491 28.815 −20.223 1.00 65.43 O HETATM 2505 O HOH C 91 −27.739 15.059 −17.377 1.00 61.15 O HETATM 2506 O HOH C 93 −5.543 19.404 −15.606 1.00 73.05 O HETATM 2507 O HOH C 95 −33.642 21.164 −32.087 1.00 61.04 O HETATM 2508 O HOH C 96 −30.337 15.575 −20.884 1.00 75.39 O HETATM 2509 O HOH C 97 −37.806 5.711 −5.034 1.00 71.43 O HETATM 2510 O HOH C 98 −38.023 22.719 −23.836 1.00 51.12 O HETATM 2511 O HOH C 99 −31.891 24.700 −31.405 1.00 67.52 O HETATM 2512 O HOH C 100 −28.164 19.674 −32.197 1.00 72.74 O HETATM 2513 O HOH C 101 −31.095 26.965 −29.990 1.00 68.13 O HETATM 2514 O HOH C 102 −27.648 17.774 −31.259 1.00 56.34 O HETATM 2515 O HOH C 103 −19.464 27.980 −42.348 1.00 82.08 O HETATM 2516 O HOH C 104 −25.287 33.732 −28.534 1.00 68.00 O HETATM 2517 O HOH C 105 −20.548 32.547 −11.654 1.00 81.80 O HETATM 2518 O HOH C 106 −11.274 14.461 −16.053 1.00 68.12 O HETATM 2519 O HOH C 107 −16.813 22.101 −23.823 1.00 45.10 O HETATM 2520 O HOH C 108 −17.466 11.687 −26.812 1.00 47.26 O HETATM 2521 O HOH C 109 −16.227 11.401 −22.646 1.00 79.59 O HETATM 2522 O HOH C 110 −22.352 17.010 −32.208 1.00 86.48 O HETATM 2523 O HOH C 111 −32.150 29.849 −17.637 1.00 58.70 O HETATM 2524 O HOH C 112 −11.387 16.284 7.657 1.00 66.65 O HETATM 2525 O HOH C 113 −3.661 22.013 −24.672 1.00 50.02 O HETATM 2526 O HOH C 114 −42.439 11.599 −29.637 1.00 70.82 O HETATM 2527 O HOH C 115 −42.938 8.633 −29.627 1.00 69.44 O HETATM 2528 O HOH C 116 −42.939 16.456 −28.113 1.00 60.92 O HETATM 2529 O HOH C 117 0.102 27.067 −30.339 1.00 74.26 O HETATM 2530 O HOH C 118 −7.692 42.195 −33.970 1.00 68.44 O HETATM 2531 O HOH C 119 −8.862 32.773 −10.234 1.00 54.83 O HETATM 2532 O HOH C 120 −10.735 30.983 −8.916 1.00 53.95 O HETATM 2533 O HOH C 121 −8.303 37.787 −17.388 1.00 61.11 O HETATM 2534 O HOH C 122 −20.041 31.220 −39.780 1.00 70.76 O HETATM 2535 O HOH C 123 −20.168 29.089 −40.470 1.00 56.82 O TER HETATM 2536 C01 LIG D 1 −6.612 14.457 −17.611 1.00 76.64 A C HETATM 2537 O02 LIG D 1 −7.363 15.243 −18.461 1.00 66.93 A O HETATM 2538 C03 LIG D 1 −7.297 16.617 −18.392 1.00 72.43 A C HETATM 2539 O04 LIG D 1 −6.466 17.159 −17.679 1.00 74.34 A O HETATM 2540 C05 LIG D 1 −8.022 17.443 −19.403 1.00 64.52 A C HETATM 2541 C06 LIG D 1 −7.375 18.741 −19.759 1.00 55.65 A C HETATM 2542 C07 LIG D 1 −6.102 18.623 −20.529 1.00 45.83 A C HETATM 2543 O08 LIG D 1 −5.801 17.548 −21.029 1.00 57.00 A O HETATM 2544 O09 LIG D 1 −5.297 19.713 −20.751 1.00 55.39 A O HETATM 2545 C10 LIG D 1 −4.201 19.565 −21.590 1.00 49.72 A C TER END

Example 5 Mass Spectrometric Analysis

RSK2 samples were reduced and alkylated with iodoacetamide, i.e. carbamidomethylated, and subsequently digested with chymotrypsin. The resulting peptides were concentrated on a ZipTip micropurification column and eluted onto an anchorchip target for analysis on a Bruker Autoflex Speed MALDI TOF/TOF instrument. The peptide mixture was analyzed in positive reflector mode for accurate peptide mass determination. MALDI MS/MS was performed on 15 peptides for peptide fragmentation analysis, i.e partial sequencing. The MS and MS/MS spectra were combined and used for database searching using the Mascot software. The data was searched against RSK2 sequence and identified based on a probability-scoring algorithm (www.matrixscience.com).

Example 6 Analysis of Mutants

Mutational analysis of MSK1 was performed in a mammalian expression vector (pEBG2T) in which a glutathione S-transferase (GST) domain and FLAG-tag (Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys) was fused to the N-terminus of human MSK1 (GST-FLAG-MSK1)⁶. The positions corresponding to C436, T579 and C599 in murine RSK2 (SEQ ID NO: 1) of human MSK1 (C440, T583 and C603) were mutated to Val, Ser and Thr (For T583 only an Ala mutation was performed) using the QuikChange Lightning Kit (Agilent Technologies).

Human embryonic kidney cells (HEK-293) were cultured in tissue culture flasks (150 cm²) to 60% confluence in Dulbecco's modified Eagle's medium (DMEM) (Gibco) supplemented with 50 units/ml penicilin G (Gibco), 50 μg/ml streptomycin (Invitrogen), 5 μg/ml gentamycin (Gibco), 10% (v/v) foetal bovine serum (FBS) (Gibco) and 2.5% HEPES (Gibco). Cells were trypsinated and seeded in 10 cm petri dishes at a density of 6.5×10⁶ cells per dish in 10 ml DMEM supplemented with 50 μg/ml bovine pituitary growth hormone (BGH) (Gibco), antibiotics (penicilin G, streptomycin, gentamycin) and 2% FBS and 2.5% HEPES and were incubated for 2 days. The culture medium was changed to 7 ml DMEM supplemented with 2.5% Hepes for 16 hours. Transfection with plasmids was performed as previously described Jensen et al. 1999⁵⁷ with modifications. HEK-293 cells were transfected using 3.5 μg plasmid DNA/dish dissolved in 250 μl Optimem (Invitrogen) and 30 μl Lipofectamine 2000 (Invitrogen) dissolved in 250 μl Optimem added together for 20 minutes before transferred to cells. The Lipofectamine and DNA complexes were incubated with cells for 6 hours at 37° C. and 5% CO₂. Cell culture medium was then changed back to 7 ml DMEM special growth medium with BGH, antibiotics, 2% FCS and 2.5% HEPES for 48 hours.

Dimethylfumarate (DMF) (Sigma-Aldrich) was dissolved in dimethylsulfoxide (DMSO) (Merck) resulting in a 70 mM stock solution and diluted to 7 mM (4% v/v DMSO) in culture medium. All stock solutions were freshly made 10 min before use. HEK 293 cells were stimulated like keratinocytes, as previously described Gesser et al. 2011⁴⁶. Cells were either left untreated or were pre-incubated with 140 μM of DMF for 1 hour and stimulated for 15 minutes for RSK2 and 30 minutes for MSK1 plasmids with 1 ng/ml of human recombinant Epidermal growth factor (EGF) (PeproTech UK). Cells were stopped after one wash with ice-cold PBS and snap-frozen in liquid nitrogen. Whole-cell extracts were prepared by adding 400 μl of 1× cell lysis sample buffer (Cell Signalling Technology) to each 10 cm dish. The 1× lysis buffer was supplemented with 22 μl protease inhibitor cocktail (EDTA-free complete, Roche Diagnostics), and 10 μl of 100 mM PMSF/ml buffer. The collected samples were sonicated and centrifuged for 10 minutes at 4° C. at 10.000 g and the supernatants were saved for protein determination. Equal loads of protein (50 μg) were separated on pre-cast gels, SDS-Page 8-16% (Invitrogen). Proteins were blotted onto Hybond nitrocellulose membrane (Amersham) and tested with antibodies as previously described (Gesser et al. 2007, 2011). Antibodies for Western Blotting: Primary antibodies were rabbit anti-phospho-MSK1 (Ser376) and rabbit anti-phospho-RSK2 (Ser386) and mouse anti-GST (26H1); Secondary antibodies were HRP anti-rabbit #7074, HRP anti-mouse #7076 (all from Cell Signalling).Densitometry analysis of the band intensity was performed on a flatbed scanner (Epson PERFECTION V750PRO) and quantitated by Jelly Quant.

For affinity purification 1 mg protein/sample, in about 300 μl/well were added to a GST affinity MultiTrap 4B 96-well filter plate (GE Healthcare). After two washes with binding buffer, proteins were eluted in 200 μl of 50 mM Tris-HCl buffer added 20 mM reduced glutathione (Sigma-Aldrich) pH 8.0 and were concentrated by freeze drying. The proteins were re-dissolved in 28 μl of 1× lysis buffer plus 14 μl of 3×SDS lysis buffer/sample and 21 μl/sample was separated on SDS-PAGE 8-16% gels. Mutational studies identified the cysteine C603, in MSK1 corresponding to C599 in murine RSK2 as vital for the inhibition of the RSK and MSK kinases by DMF.

Example 7 Docking and in Silico Screening

Two grids is calculated using Maestro version 8.0 with Exhaustive Sampling of Optimize H-bonds, one grid with Minimize structure within 0.3 Å and one without Minimize for the refined structure of DMF bound to RSK2. The bounding box is defined as the centroid of residue C599 with standard value dimensions.

Ligands are built in Maestro as fumaric acid ester derivatives, resulting in 100 compounds. Ligands are energy minimized in MacroModel with the OPLS_(—)2005 force field and maximum iterations set to 10000.

Docking is performed into all the grids generated using the XP scoring function. Constraints are applied so that a C—S bond was formed between the ligand and RSK2. Derivatives are chosen for synthesis and in vitro testing based on both G-score and manual inspection of the docking pose. Additionally, consistently poorly scoring/docking ligands that are very similar to those chosen for synthesis are also synthesized as negative controls. Docking and in silico screening identifies potential drug candidates.

Example 8 In Vitro Test of Drug Candidates 1

Normal adult human keratinocytes were obtained by trypsinization of skin samples from patients undergoing surgery as described earlier (Kragballe et al. 1985⁶¹) First passage keratinocytes are grown in keratinocyte serum-free medium (Invitrogen) added supplement (Gibco 37000-15) and 5 μg/ml gentamycin (Gibco) to 60% confluence. Cells are then trypsinated and seeded in 6-well plates at 400×10³ cells/well in keratinocyte basal medium (Gibco 37000-015), supplemented with only bovine pituitary growth hormone (Gibco 15710), 50 μg/ml bovine pituitary extract (Gibco), 5 μg/ml gentamycin and 2% FCS (Gibco) as described before ⁵¹. After 24 h, cells are pre-incubated with vehicle or drug candidates (1, 10 and 100 μM) for 1 hour and stimulated with 2 ng/ml human recombinant EGF (AF-100-15, PeproTech EC, London, UK) for 5, 15 and 30 min as described before ⁵¹. cells were collected after wash with ice-cold PBS and snap-frozen in liquid nitrogen. Whole cell extracts are prepared in 100 μl of sample buffer as previously described ³⁹

Alternatively, cells are left alone or pre-incubated with drug candidates for 1 h and then stimulated with IL-1β (20 ng/ml)(Pepro Tech INC) or rh-TNF-α (10 ng/ml) (R&D Systems, Minneapolis) for 0, 5, 15 or 30 min as described before ³⁹

Equal loads of proteins (50 μg/lane) are separated on 8-16% SDS-PAGE Tris-glycine gels (Invitrogen) and after Western Blotting probed with anti-p-MSK1 (S376) and anti-p-RSK2 (S386) antibodies as previously described ⁵¹.

Drug candidates are solubilised in DMSO 100 mM (Sigma-Aldrich) and diluted to 1 mM stock solution (2% v/v DMSO) in keratinocyte basal medium 10 minutes before use. Drug candidates are directly added to cell culture medium to final concentration of 1, 10 and 100 μM.

Example 9 In Vitro Test of Drug Candidates 2

Peripheral blood mononuclear cells (PBMCs) are purified by Lymphoprep density gradient media (Axis-Shield) from EDTA blood of normal human donors as described before. Cells are washed with cold sterile Dulbecco's PBS (Gibco) and seeded at 6×10⁶ cells/petri dish in 10 ml RPMI 1640 (Gibco) supplemented with penicillin (10,000 units/ml), streptomycin (10 mg/ml) (Gibco) and gentamycin (2.5 mg/ml) in 10² cm petri dishes. Cells are pre-incubated with vehicle or drug candidates (1, 10 100 μM) for 1 h and either left alone or stimulated with 10 ng/ml IL-1β. (R&D Systems) or 2 ng/ml EGF (Gibco) for 0, 10 and 20 minutes. After stimulation, petri dishes are placed on ice and cells are collected by ice cold Dulbecco's PBS and centrifuged 1400 rpm for 10 minutes. Supernatants are removed and cells are added 100 μl of 1× cell Lysis sample buffer (Cell Signalling Technology)/sample. After protein determination, 20 μg protein/lane is separated on 8-16% SDS-PAGE Tris-glycin gels (Invitrogen) and after Western Blotting probed with anti-p-MSK1 (S376) and anti-p-RSK2 (S386) antibodies as previously described ⁵¹. Drug candidates are solubilised in DMSO (Sigma-Aldrich) 100 mM and diluted to 1 mM stock solution (2% v/v DMSO) in RPMI 1640 medium 10 minutes before use. Drug candidates are directly added to cell culture medium to final concentration of 1, 10 and 100 μM.

Example 10 In Vivo Test of Drug Candidates

Experimental autoimmune encephalomyelitis (EAE), a reliable and widely used mouse-model of multiple sclerosis (MS) and is similarly to Schilling et al. 2006⁷ carried out. EAE is induced in mice by s.c. injections in the flanks and tail base of 50 μg MOG 35-55 peptide in PBS emulsified in an equal volume of complete Freund's adjuvant (CFA) containing Mycobacterium tuberculosis H37RA (Difco) at a final concentration of 0.5 mg/ml. Two injections of 200 ng per mouse i.p of pertussis toxin (List Biological Laboratories Inc.) are given on days 0 and 2. Animals are weighed and scored for clinical signs of disease on a daily basis as previously described. Drug candidates are freshly diluted in 200 μl 0.08% Methocel (DOW)/H₂O (before use) and is used as vehicle and administered by oral gavage starting from day 3 post immunization (p.i) until termination. Each treatment group consists of 8 animals: vehicle alone as a negative control, 5 mg/kg body weight drug candidate twice a day, 15 mg/kg body weight drug candidate twice a day. The lower drug candidate dose is correlated to the dose used in human psoriasis in clinical trials. The threefold higher dosage of drug candidate was used to compensate for body surface disparity of mice. Oral gavage is used to ensure exact dosing and to avoid compound degradation. Mice are deeply anaesthesized with ketamine/xylazine hydrochloride in the early chronic phase and perfused with saline followed by 4% of paraformaldehyde. The complete spinal cord is carefully removed and axial sections were paraffin embedded. Paraffin sections are subjected to haematoxylin/eosin (H&E) staining to assess parameters of inflammatory infiltrates.

REFERENCES

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1. A three dimensional crystal of a complex between: a) one or more fumaric acid derivative ligand, and b) a polypeptide comprising the sequence of SEQ ID NO: 1 (C-terminal kinase domain of murine ribosomal S6 kinase 2), or a biologically active structural and/or functional variant thereof, wherein the biological activity is kinase activity.
 2. The crystal according to claim 1, wherein the structural and/or functional variant is a ribosomal S6 kinase (RSK) or a mitogen- and stress-activated protein kinase (MSK) polypeptide.
 3. The crystal according to any one of the preceding claims wherein the structural and/or functional variant is selected from the group consisting of: a) an amino acid sequence selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
 18. 19 and 20; or b) a sequence variant of the polypeptide of a), wherein the sequence variant has at least 70% sequence identity to SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
 18. 19 or 20; or c) a fragment of the polypeptide of a) or b), wherein the fragment comprises at least 100 contiguous amino acids of any one of a) or b), and wherein the biological activity is kinase activity.
 4. The crystal according to any one of the preceding claims wherein the variant has at least 70%, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
 18. 19 and
 20. 5. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y197, A200, C201, W204, I235, H263, V264, R269 or L312 of SEQ ID NO.
 1. 6. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y196, A199, C200, W203, I234, H262, V263, R268 or L311 of SEQ ID NO.
 2. 7. The crystal according to one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y591, G594, C595, W598, I629, H657, V658, R663 or L705 of SEQ ID NO.
 3. 8. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667 or L710 of SEQ ID NO.
 4. 9. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, 626, H654, V655, R660 or L702 of SEQ ID NO.
 5. 10. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y599, A602, C603, W606, I637, H665, M666, R671 or L714 of SEQ ID NO.
 6. 11. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y599, S602, C603, W606, I641, T669, V670, R675 or F722 of SEQ ID NO.
 7. 12. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO.
 8. 13. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y580, G583, C584, W587, I618, H646, V647, R652 or L694 of SEQ ID NO.
 9. 14. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667, L710 of SEQ ID NO.
 10. 15. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, I626, H654, V655, R660 or L702 of SEQ ID NO.
 11. 16. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y619, A622, C623, W626, I657, H685, M686, R691 or L731 of SEQ ID NO.
 12. 17. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y663, S666, C667, W670, I705, T733, V734, R739 or F786 of SEQ ID NO.
 13. 18. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO.
 14. 19. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y591, G594, C595, W598, I629, H657, V658, R663 or L705 of SEQ ID NO.
 15. 20. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667 or L710 of SEQ ID NO.
 16. 21. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, I626, H654, V655, R660 or L702 of SEQ ID NO.
 17. 22. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y716, A719, C720, W723, I754 or H782 or M783 or R788 or L828 of SEQ ID NO.
 18. 23. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y575, A578, C579, W582, I617, T645, V646, R651 and F698 of SEQ ID NO.
 19. 24. The crystal according to any one of the preceding claims wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO.
 20. 25. The crystal according to any one of the preceding claims, wherein the polypeptide is folded into tertiary structure.
 26. The crystal according to any one of the preceding claims, further comprising an affinity tag, such as a polyhistidine tag, a GST tag, a HA tag, a Flag tag, a C-myc tag, a HSV tag, a V5 tag, a maltose binding protein tag, a cellulose binding domain tag.
 27. The crystal according to any one of the preceding claims, further comprising a polyhistidine tag.
 28. The crystal according to any one of the preceding claims wherein the poly-histidine tag is an N-terminal poly-histidine tag.
 29. The crystal according to any one of the preceding claims wherein the poly-histidine tag is a C-terminal poly-histidine tag.
 30. The crystal according to any one of the preceding claims, wherein the polypeptide comprises a protease cleavage site allowing the affinity tag to be removed.
 31. The crystal according to any one of the preceding claims, wherein the protease cleavage site is a Tobacco Etch Virus protease site.
 32. The crystal according to any one of the preceding claims wherein the ligand is selected from the group consisting of dimethyl fumarate (DMF) and derivatives thereof.
 33. The crystal according to any one of the preceding claims wherein the ligand is a kinase inhibitor.
 34. The crystal according to any one of the preceding claims wherein the ligand is capable of inhibiting the biological activity of one or more of the polypeptides selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and
 20. 35. The crystal according to any one of the preceding claims wherein said crystal is of a tetragonal space group.
 36. The crystal according to any one of the preceding claims wherein said crystal is of space group P4₁2₁2.
 37. The crystal according to any one of the preceding claims wherein the unit cell parameters are a=b=47 Å±3 Å, c=292 Å±5 Å and α=β=γ=90°±2°.
 38. The crystal according to any one of the preceding claims wherein the unit cell parameters are a=b=46.95 Å±3 Å, c=291.87 Å±5 Å and α=β=γ=90°±2°.
 39. The crystal according to any one of the preceding claims wherein the unit cell parameters are a=b=46.95 Å, c=291.87 Å and α=β=γ=90°.
 40. A method for growing a crystal according to any one of the preceding claims, comprising the steps of: a) obtaining a composition comprising 5 to 15 mg/mL of a polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 or a fragment or variant thereof, in a suitable buffer b) contacting the composition of a) with a ligand as defined in any one of claims 29 to 31, c) allowing time for formation of a protein-ligand complex in solution, d) mixing the solution comprising the protein-ligand complex of c) with a reservoir solution comprising a precipitant and a buffer, e) incubating a drop of the mixture of d) under vapour diffusion conditions versus the reservoir solution, f) obtaining crystals of the protein-ligand complex.
 41. The method according to claim 40, further comprising pre-treating the polypeptide with a reducing agent.
 42. The method according to any one of claims 40 and 41, wherein the reducing agent is tris(2-carboxyethyl)phosphine (TCEP).
 43. The method any one of claims 40 to 42, wherein the reservoir solution is an aqueous solution of: a) 0.1 M Bis-Tris pH 6.5, HEPES pH=7.0, or b) TrisHCl pH=8.5 and 25% (w/v) polyethylene glycol (PEG)
 3350. 44. The method according to any one of claims 40 to 43 wherein equal volumes of protein-ligand complex and reservoir solution are mixed in step d).
 45. The method according to any one of claims 40 to 44, wherein the equal volumes are both 0.2-4 μl.
 46. The method according to any one of claims 40 to 45, wherein the method is performed at room temperature (18-25° C.).
 47. The method according to any one of claims 40 to 46, further comprising a step of optimizing the crystal size and diffraction properties by contacting the crystal an additive.
 48. The method according to any one of claims 40 to 47 wherein the additive is an aqueous solution of 0.01-0.1 M NaF.
 49. The method according to any one of claims 40 to 48 wherein the methionine residues of the polypeptide are replaced by seleno-methionine.
 50. The method according to any one of claims 40 to 49, further comprising the steps of: a) isolating an initial precipitate and b) growing these by vapour diffusion from hanging or sitting drops.
 51. A computer-based method for rational drug design which comprises: a) providing the atomic coordinates of the polypeptide as defined by table 3; b) providing the structure of a candidate inhibitor molecule; and c) fitting the structure of candidate inhibitor molecule to the atomic coordinates of the polypeptide of said table.
 52. A computer-based method for identifying a potential inhibitor of the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 comprising the steps of: a) employing a three-dimensional structure of the polypeptide, the three-dimensional structure being defined by atomic coordinate data according to table 3; and b) identifying the potential inhibitor by designing or selecting a compound for interaction with the active site.
 53. The method of claim 52 further comprising: a) obtaining or synthesizing the potential inhibitor; b) contacting the potential inhibitor with the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 to determine the ability of said inhibitor to interact with said polypeptide.
 54. The method of claim 52 which further comprises: a) obtaining or synthesising said potential inhibitor; b) forming a complex of said polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; and said potential inhibitor; and c) analysing said complex by X-ray crystallography to determine the ability of said potential inhibitor to interact with said polypeptide.
 55. A computer readable media with either: a) atomic coordinate data according to table 3 recorded thereon, said data defining the three-dimensional structure of the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, at least one atom or at least one sub-domain thereof, or b) structure factor data for the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 recorded thereon, the structure factor data being derivable from the atomic coordinate data of table
 3. 56. A computer-readable data storage medium comprising a data storage material encoded with at least a portion of the structure coordinates set forth in table
 3. 57. A method for identifying a ligand capable of binding to the binding site of SEQ ID NO. 1 (C-terminal domain of murine RSK2), said method comprising the steps of: a) generating the spatial structure of the binding site on a computer screen using atomic coordinates as presented in table 3 or atomic coordinates selected from a three-dimensional structure that deviates from the three-dimensional structure presented in table 3 by a root mean square deviation over protein backbone atoms of not more than 3 Å, b) generating potential ligands with their spatial structure on the computer screen, and c) selecting ligands that can bind to at least 1 amino acid residue of the set of binding interaction sites without steric interference.
 58. A computer-assisted method for identifying a ligand of a polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, using a programmed computer comprising a processor, a data storage system, a data input device and a data output device, comprising the following steps: a) inputting into the programmed computer through said input device data comprising: atomic coordinates of a subset of the atoms of said polypeptide, thereby generating a criteria data set; wherein said atomic coordinates are selected from the three-dimensional structure presented in table 3 or atomic coordinates selected from a three-dimensional structure that deviates from the three-dimensional structure presented table 3 by a root mean square deviation over protein backbone atoms of not more than 3 Å, b) comparing, using said processor, the criteria data set to a computer data base of low-molecular weight organic chemical structures and peptide fragments stored in the data storage system; and c) selecting from said database, using computer methods, a chemical structure having a portion that is structurally complementary to the criteria data set and being free of steric interference with the polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and
 20. 59. A method for identifying a ligand, said method comprising the steps of: a) selecting a potential ligand using atomic coordinates in conjunction with computer modelling, wherein said atomic coordinates are the atomic coordinates presented in table 3 or wherein the atomic coordinates are selected from a three-dimensional structure that deviates from the three-dimensional structure presented in any of table 3 by a root mean square deviation over protein backbone atoms of not more than 3 Å, by docking potential ligands into a set of binding interaction sites the binding site of said polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, said binding interaction generated by computer modelling and selecting a potential ligand capable of binding to at least one amino acid in said set of binding interaction sites of said polypeptide selected from the group consisting of SEQ ID NO. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, b) providing said potential ligand and said polypeptide, c) contacting the potential ligand with said polypeptide and d) detecting binding of said polypeptide by the potential ligand.
 60. The method according to any one of claims 51 to 59, wherein the atomic coordinates are determined to a resolution of at least 5 Å, preferably at least 4 Å, more preferably at least 3 Å, more preferably at least 2 Å, more preferably at least 1.5 Å.
 61. The method according to any one of claims 51 to 60, wherein the potential inhibitor is selected from the group consisting of non-hydrolyzable peptides and peptide analogues, organic compounds and inorganic compounds.
 62. The method according of any one of claims 51 to 61, wherein a library of small organic molecules are screened.
 63. The method according to any one of claims 51 to 61, wherein a library of potential peptide ligands are screened.
 64. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y197, A200, C201, W204, I235, H263, V264, R269 or L312 of SEQ ID NO.
 1. 65. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y196, A199, C200, W203, I234, H262, V263, R268 or L311 of SEQ ID NO.
 2. 66. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y591, G594, C595, W598, I629, H657, V658, R663 or L705 of SEQ ID NO.
 3. 67. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667 or L710 of SEQ ID NO.
 4. 68. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, 626, H654, V655, R660 or L702 of SEQ ID NO.
 5. 69. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y599, A602, C603, W606, I637, H665, M666, R671 or L714 of SEQ ID NO.
 6. 70. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y599, S602, C603, W606, I641, T669, V670, R675 or F722 of SEQ ID NO.
 7. 71. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO.
 8. 72. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y580, G583, C584, W587, I618, H646, V647, R652 or L694 of SEQ ID NO.
 9. 73. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667, L710 of SEQ ID NO.
 10. 74. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, I626, H654, V655, R660 or L702 of SEQ ID NO.
 11. 75. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y619, A622, C623, W626, I657, H685, M686, R691 or L731 of SEQ ID NO.
 12. 76. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y663, S666, C667, W670, I705, T733, V734, R739 or F786 of SEQ ID NO.
 13. 77. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO.
 14. 78. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y591, G594, C595, W598, I629, H657, V658, R663 or L705 of SEQ ID NO.
 15. 79. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y595, A598, C599, W602, I633, H661, V662, R667 or L710 of SEQ ID NO.
 16. 80. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y588, A591, C592, W595, I626, H654, V655, R660 or L702 of SEQ ID NO.
 17. 81. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y716, A719, C720, W723, I754 or H782 or M783 or R788 or L828 of SEQ ID NO.
 18. 82. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y575, A578, C579, W582, I617, T645, V646, R651 and F698 of SEQ ID NO.
 19. 83. The method according to any one of claims 51 to 63, wherein the one or more ligand(s) is located in a binding site comprising amino acid residues Y586, S589, C590, W593, I628, T656, V657, R662 or F709 of SEQ ID NO.
 20. 84. The method or the computer readable media according to any one of claims 51 to 83, wherein the coordinates of table 3 have been modified to provide a ligand free pdb file.
 85. The method or the computer readable media according to claim 84, wherein the ligand free pbd file is used in the method of any one of claims 51 to
 83. 